Expert Review of Vaccines

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The durability of vaccine-induced protection: an

overview

Vipin M. Vashishtha & Puneet Kumar

To cite this article: Vipin M. Vashishtha & Puneet Kumar (2024) The durability of
vaccine-induced protection: an overview, Expert Review of Vaccines, 23:1, 389-408, DOI:
10.1080/14760584.2024.2331065

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EXPERT REVIEW OF VACCINES
2024, VOL. 23, NO. 1, 389–408
https://doi.org/10.1080/14760584.2024.2331065

REVIEW

The durability of vaccine-induced protection: an overview

a
Vipin M. Vashishtha and Puneet Kumarb
a
Department of Pediatrics, Mangla Hospital & Research Center, Shakti Chowk, Bijnor, Uttar Pradesh, India; bDepartment of Pediatrician, Kumar
Child Clinic, New Delhi, India

ABSTRACT ARTICLE HISTORY

Introduction: Current vaccines vary widely in both their efficacy against infection and disease, and the Received 18 January 2024
durability of the efficacy. Some vaccines provide practically lifelong protection with a single dose, while Accepted 12 March 2024
others provide only limited protection following annual boosters. What variables make vaccine-induced
KEYWORDS
immune responses last? Can breakthroughs in these factors and technologies help us produce vaccines
Durability; immunity;
with better protection and fewer doses? The durability of vaccine-induced protection is now a hot area immune responses;
in vaccinology research, especially after COVID-19 vaccines lost their luster. It has fueled discussion on persistence of immunity;
the eventual utility of existing vaccines to society and bolstered the anti-vaxxer camp. To sustain public vaccines; vaccinology
trust in vaccines, lasting vaccines must be developed.
Areas covered: This review summarizes licensed vaccines’ protection. It analyses immunological
principles and vaccine and vaccinee parameters that determine longevity of antibodies. The review
concludes with challenges and the way forward to improve vaccine durability.
Expert opinion: Despite enormous advances, we still lack essential markers and reliable correlates of
lasting protection. Most research has focused on humoral immune responses, but we must also focus
on innate, mucosal, and cellular responses – their assessment, correlates, determinants, and novel
adjuvants. Suitable vaccine designs and platforms for durable immunity must be found.

1. Introduction 2. Overview of the durability of protection

‘Waning of immunity’ became a buzzword not only in academia
and industry but also among the lay public when it became clear
that the protection conferred by COVID-19 vaccines is not as
durable as offered by other vaccines like measles. The excitement
over the speedy development and rapid deployment of COVID-19
vaccines gradually waned off, and soon, a debate surrounding the
durability of immune protection ensued. Thus, the durability of
vaccine-induced protection is a hot area of research today. What
factors determine the durability of vaccine-induced immune pro­
tection? Does the nature of the pathogen (fast mutating virus vs.
‘stable’ virus), the biology of the vaccine (live attenuated vs. inacti­
vated viral vaccine, the addition of an adjuvant and the type), or
the vaccination schedule (dose, number of doses and interval
between doses) have any bearing on the long term persistence
of vaccine-derived immunity? It is also known that natural infec­
tions caused by most human coronaviruses, including Severe
Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) and influ­
enza, fail to provide long-lasting protection, unlike other respira­
tory pathogens like measles, rubella, varicella, and mumps [1]. The
current generation of vaccines against all these pathogens also
follows a similar pattern.
This review provides an overview of the durability of protection
offered by the currently used licensed vaccines. It summarizes the
current knowledge, recent advances, knowledge gaps, challenges,
and bottlenecks regarding the long-term protection induced by
vaccines and how to overcome these.
conferred by the key licensed vaccines
To perform an analysis of the durability of immune protection
accorded by the currently licensed vaccines, we have broadly
classified them under three heads (Table 1):
(1) Vaccines that provide long duration of protection (>20
years).
(2) Vaccines that provide moderate duration of protection
(5-20 years).
(3) Vaccines that provide short duration of protection (<5
years).
2.1. Vaccines that provide a long duration of protection
(>20 years)
2.1.1. Measles vaccines
A single dose of vaccine offers lifelong protection to nearly all
vaccinees. The primary immune response is boosted with
exposure to wild viruses or after re-vaccination [2]. Once ser­
oconverted, protective anti-measles antibodies ≥ 120 mIU/mL
are detected for a very long period, probably for life, without
any significant waning in the antibody titers. A modeling
study estimated the half-life of anti-measles antibodies to be
more than 3000 years [3].

CONTACT Vipin M. Vashishtha vipinipsita@gmail.com Director and Consultant Pediatrician, Department of Pediatrics, Mangla Hospital & Research Center,
Shakti Chowk, Bijnor, Uttar Pradesh 246701, India
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
390 V. M. VASHISHTHA AND P. KUMAR
Article highlights
● Only a handful of currently licensed vaccines provide long-lasting
protection
● There are still gaps in our understanding of reliable correlates of
durable protection.
● Induction of vigorous germinal center reaction and induction of
a large number of long-lasting plasma cells along with the formation
of memory B-cells and memory T-cells is essential for durable vac­
cine-induced protection
● There are several determinants of the longevity of antibody response,
such as vaccine platform, target pathogen, vaccinee’s characteristics,
environmental and genetic factors
● New developments in the field of vaccinology, like improved vaccine
design, novel adjuvants, and molecular delineation of antigenic
forms, hold hope for developing durable vaccines
● Further research is needed to identify the optimal antigen delivery
methods and formulations that result in prolonged antigen availabil­
ity and can elicit long-lasting and protective immunity
2.1.5. Rubella vaccine
Rubella vaccine also induces a robust immune response that is
presumed to be lifelong [4]. Rubella virus-specific humoral
immune responses wane with time after vaccination, but they
do so moderately [5]. Though no absolute immune correlate of
protection has been established, a cutoff level of anti-rubella
IgG antibodies of ≥ 10 IU/mL is generally protective against
rubella disease [4]. One longitudinal study estimated that
rubella-specific immunity was maintained, with an estimated
half-life of 114 years and no significant rate of titer decrease [3].
2.1.3. Yellow fever vaccine
The live-attenuated yellow fever vaccine has excellent long-
term effectiveness. The titer of neutralizing antibodies is the
correlate of protection. Plaque reduction neutralization test
(PRNT50) assays with a titer of 1 in 10 are used in most clinical
trials to correlate protection.
According to Poland et al. [6], 80.6% of World War II
soldiers had neutralizing antibodies that lasted longer than
thirty years. Neutralizing antibodies have also shown long-
term persistence in several additional studies conducted in
both endemic and non-endemic countries [7–10]. Since
there are no documented cases of Yellow Fever infection
in individuals with documented seroconversion, it has been
argued that the hypothesis that the vaccine provides life­
long protection is correct [11].
2.1.4. Hepatitis-B vaccine
The Hepatitis B vaccine is a T-cell-dependent subunit vaccine,
and hepatitis B infection has a long incubation period, allow­
ing enough time for an anamnestic response to occur if there
is contact with the virus. Hence, once seroconversion occurs,
the vaccine can provide long-term protection even if antibody
titers fall below the protective level of 10mIU/mL.
2.1.5. Hepatitis-A inactivated vaccine
Many modeling and anti-HAV kinetic studies have confirmed
that a high level of seroprotection can be achieved for at least
30 years by a single or two-dose vaccine schedule [12,13].
Furthermore, protection against the clinical disease may per­
sist even without detectable antibodies in the presence of
memory B and T cells [14].
2. Vaccines that provide moderate duration of
protection (5–20 years)
2.2.1. Oral polio vaccine (OPV)
After seroconversion, OPV offers almost lifelong protection
against paralytic poliomyelitis, even if the antibody titers fall
below detectable levels later in life. However, seroconversion
and efficacy vary between different geographical settings:
higher in temperate climates in industrialized countries than
in developing countries with tropical conditions. According to
an Italian study, immune protection against paralytic disease
persisted up to 18 years after administration of the last OPV
dose, with protective antibodies against poliovirus type 1 and
2 detected in more than 95% of the subjects even after 30
years of the last OPV dose [15].
2.2.2. Inactivated poliovirus vaccine (IPV)
Studies from industrialized countries have indicated that IPV-
induced antibodies protect from paralytic polio for many dec­
ades, probably for life [16]. According to a retrospective cohort
study from Italy, neutralizing antibodies against all three polio
types persisted in more than 90% of study participants 18
years after the last vaccine dose [17]. In this study, the IPV
induced higher titers of neutralizing antibodies than OPV.
2.2.3. Hepatitis A live attenuated vaccine
Like inactivated vaccines, live attenuated hepatitis-A vaccines
also offer a long duration of protection. After a single dose of
H2 strain-based live attenuated vaccine in an endemic region,
at least 15–17 years of protection has been demonstrated
along with the persistence of immune memory [18–20].
2.2.4. Human papilloma virus (HPV) vaccines
These vaccines are unique in that they offer long-lasting pro­
tection against HPV-related illnesses even with a single dose,
and the protection they offer is virtually sterilizing, meaning
that they prevent infection rather than just illness [21]. This is
despite them being non-live attenuated vaccines. Bivalent,
quadrivalent, and nonavalent vaccines have shown the most
extended durations of preventative effect: 11 years in the
Costa Rica trial [22], 14 years in the FUTURE II trial [23], and
eight years in the long-term follow-up (LTFU) extension study
[24] and Scandinavian Study [25]. An Australian real-world
effectiveness study [26] has the longest observation time of
12 years for vaccine efficacy (for the quadrivalent vaccine).
2.2.5. Bacille Calmette-Guérin (BCG) vaccine
Even while the BCG vaccine’s efficacy varies greatly depending
on the clinical entity and demography, it offers quite a long
period of protection – even up to 50 years [27–29]. A thorough
analysis found that in certain groups, protection following
a baby BCG vaccine could continue up to 15 years; neverthe­
less, the protective efficacy does eventually wane [30].
Table 1. A summary of currently licensed vaccines grouped based on their duration of protection, along with other vital parameters.
Estimated duration of protection
Correlate of Efficacy Duration of
Number Vaccine Vaccine type protection (CoP) (point estimate) Clinical entity protection Comments
(I) Vaccines that provide long duration of protection (>20 years).
1. Measles vaccine Live attenuated parenteral ≥120 miU/ml 83% (95% CI: 76–88) Measles infection Lifelong protection Boosting of primary immune response is seen with exposure to
vaccine and disease after wild virus or after re-vaccination
seroconversion
2. Rubella Live attenuated parenteral Abs ≥10-15IU/ml 80.7%, (95% CI: 73.7– Rubella infection Lifelong protection Rubella virus-specific humoral immune responses wane with time
vaccine 85.8%) after vaccination, but they do so at a moderate rate.
3. Yellow Fever Live attenuated vaccine (17D log10 neutralization ~99% Yellow fever Lifelong protection Some waning after 10 years. Boosters were recommended after
Vaccine strain) index (LNI) of ≥0.7 disease 10 years till recently.
4. Hepatitis-B Inactivated, sub-unit ≥10 mIU/mL Against infection: 89% Hepatitis-B disease Up to 30 years After 3 doses
Against chronic
carriage: 96%
5. Hepatitis- Inactivated vaccine ELISA Ab 20mlU/ml >98% Hepatitis At least 25 years Mathematical modeling suggests that detectable antibodies are
A-inactivated A infection estimated to persist for as long as 60 years for the 2-dose
schedules.
II. Vaccines that provide moderate duration of protection (5–20 years).
1. Oral Polio Vaccine Live attenuated, oral ≥1/8 dilution of 72% (95%CI: 57–82) Paralytic polio Up to 18 years Data limited from the tropical countries
NAbs
2. Inactivated Polio Inactivated ≥1/8 dilution of 89% (95% CI 62%, 97%) Paralytic polio At least 18 years Limited studies from the developing and tropical countries
vaccine NAbs with two doses:
3. Hepatitis-A-live Live attenuated vaccine (H2 ELISA Ab 20mlU/ml 100% Hepatitis At least 15–17 After a single dose of H2 strain based live attenuated vaccine in
attenuated strain) A infection years endemic region.
Protection may persist longer. Trials on longevity of immunity
are still ongoing.
4. Human Inactivated, ND For HPV naive at HPV vaccine- 11–14 years Longitudinal trials are still ongoing. The longest period of
papillomavirus Virus-like particle (VLP) enrollment: 91–100% induced (following full preventive effect for the bivalent, 4-valent, and 9-valent
(HPV) vaccine based (64.6% to 86%; 94.2% seropositivity course) vaccine were 11 years in the Costa Rica trial, 14 years in the
to 100) FUTURE II, and 8 years in the LTFU extension study and the
Scandinavian study, respectively.
5. BCG Live attenuated, ID ND 37% for all forms of Pulmonary & 10–15 years Protection may last longer, may be up to 50–60 years though
(IFNγ-production tuberculosis (TB) in extrapulmonary waning of efficacy does occur.
by CD4 T cells) children below 5 years TB
of age
42% against pulmonary
disease in children
below 3 years of age
6. Diphtheria Toxoid 0.01–0.1 IU/ml 95.5% (95% CI 92%, Diphtheria disease 11 years After primary series and two booster doses
97.4%
7. Tetanus Toxoid 0.1 IU/ml Virtually 100% Tetanus disease 10 years After three primary doses and two boosters
8. Varicella zoster Live attenuated parenteral GP ELISA ≥5 U/ml 98% All chickenpox Around 10 years Several studies have shown that vaccinated people had varicella
vaccine vaccine disease (after single antibodies for at least 10 to 20 years after vaccination. But
dose) these studies were done before the vaccine was widely used
and when infection with wild-type varicella was still very
common.
9. Mumps Live attenuated parenteral ND 75.8% (35.6%, 90.9%) Mumps disease 6–7 years It is estimated that 85% protection is there 6–7 years after 2
vaccine with Urabe strain and doses of the vaccine and decrease to pre-vaccination level by
64.7% (10.6%, 86.0%) 12 years in the absence of natural boosting
for Jeryl-Lynn strain
EXPERT REVIEW OF VACCINES

10. Pneumococcal Inactivated, polysaccharide 0.20–0.35 mcg/ml 80% (95% CI58–90) Pneumococcal More than 6 years Exact duration of protection is not known; marked variation in the
conjugate conjugate, subunit vaccine (ELISA for Abs) disease protection rates of different serotypes
Vaccine
(Continued )
391
 392

Table 1. (Continued).
Estimated duration of protection
Correlate of Efficacy Duration of
Number Vaccine Vaccine type protection (CoP) (point estimate) Clinical entity protection Comments
11. Rabies Inactivated, (Cell culture & NAbs: ≥0.5 IU Virtually 100% Rabies infection 9 years Vaccine induced memory B cells appear to persist for life.
embryonated egg-based Effective recall of the immune response to additional doses,
rabies vaccines (CCEEVs) such as for Post-exposure prophylaxis (PEP), are documented
for decades after priming.
12. Herpes Zoster Recombinant subunit ND 97.2% (95% CI, 93.7–99.0; Herpes Zoster 10 years Unlike the live attenuated vaccine, the high efficacy found even
(recombinant) (glycoprotein E) vaccine p<0.001) Herpes Zoster after 10 years of primary vaccination.
vaccine with AS01 adjuvant ophthamicus
system Post herpetic
neuralgia
13. Pertussis-Whole Inactivated, whole cell ND 94% (95%CI: 88–97%) Pertussis infection 4–12 years After primary series and childhood boosters
V. M. VASHISHTHA AND P. KUMAR

cell vaccines
14. Pneumococcal Inactivated, polysaccharide ND 74% (95% CI: 54–85) Pneumococcal 5–8 years The VE in older adults diminishes in the years following
polysaccharide subunit vaccine diseases vaccination and is likely absent after some interval, which may
vaccine (PPSV) be on the order of 5 or more years.
15. H. influenzae type Inactivated, polysaccharide 0.15 mcg/ml 95–100% (95%CI: 55–100) H. influenzae Up to 6 years after Although vaccine effectiveness declined significantly after the
‘b’ conjugate conjugate, subunit vaccine disease a booster in 2nd first year of life (p<.001), it remained high until the sixth year of
vaccine year life
III. Vaccines that provide short duration of protection (<5 years)
1. Meningococcal Quadrivalent Subunit Serum bactericidal 79% (49% to 91%) at Meningococcal ~5 years Waning of Vaccine efficacy varies with serotype and vaccinees’
vaccine vaccine: Bacterial capsular titer of ≥1:8 using <1 year post single Meningitis, age: faster waning in children < 7 years than at older age
oligosaccharides baby rabbit dose meningococcal
conjugated to a carrier complement fulminant
protein (rSBA) septicemia
2. Pertussis-acellular Inactivated, sub-unit vaccine ND 84% (95%CI: 81–87%) Pertussis infection 4–7 years Evidence of waning of immunity beyond 4 years and little-to-no
vaccines & disease protection beyond 7 years from last vaccination
Primary series, followed by two boosters
3. Dengue vaccine Live attenuated ND 62.0% (95% CI, 56.6–66.7) Virologically 5 years in Waning of protection
(CYD-TDV) viral vaccine (NAbs, variable) at 1 year confirmed seropositive Efficacy varies by sero-status and severity of disease
(CYD-TDV-Dengvaxia ) ® dengue
4. Dengue vaccine Live attenuated tetravalent ND 82.2% (95% CI: 87.6– Virologically 4.5 years Waning of protection
(TAK-003) dengue vaccine (TAK-003, (NAbs, variable) 74.5%) at one year confirmed Efficacy varies by sero-status and severity of disease
Qdenga )™ dengue
5. Cholera vaccine, Whole cell killed vaccine ND 67% Cholera 5 years The combined VE after 5 years was estimated to be 65%
bivalent (Vibriocidal Abs)
6. Cholera vaccine, Whole cell killed vaccine ND 85% Cholera 6 month to 5 years The protection lasts only 6 months for children and 2 years in
monovalnt with recombinant (Vibriocidal Abs) adults.
B subunit of cholera toxin
7. Japanese Live attenuated NAbs: 1:10 (PRNT) 98.5% (CI 90.1–99.2%) JE disease 5 years Recent studies from India find showed a decreasing trend of anti-
encephalitis SA 14-14-2 vaccine (after a single JEV specific IgG antibody titers following two doses of SA-14-
vaccine-live dose) 14-2 vaccine. Marked waning in titers noted after even 2 years
of vaccination
8. Japanese Inactivated NAbs: 1:10 (PRNT) 91% (95% CI: 70–97) JE disease 5 years (after 2 −2 dose primary series in adults from non-endemic regions
encephalitis (IXIARO /JESPECT /
® ® primary doses) –Modeling suggests protection may last up to 14 years after
vaccine- JEEV ) ® booster at 15 mo
Inactivated
9. Typhoid conjugate Inactivated, polysaccharide ND 81.6%; (95% CI: 58.8 to Typhoid fever Around 5–7 years Definite waning in anti-Vi IgG antibodies seen after 5 years. To
vaccine conjugate, subunit vaccine 91.8) extend protection, administering a booster dose to children ∼5
years after their primary dose may be considered
(Continued )
Table 1. (Continued).
Estimated duration of protection
Correlate of Efficacy Duration of
Number Vaccine Vaccine type protection (CoP) (point estimate) Clinical entity protection Comments
10. Typhoid Typhoid polysaccharide ND 69% (95% CI = 28–87%) Typhoid fever 3 years To maintain protection, revaccination is recommended every 3
unconjugated vaccines years.
Vi-
polysaccharide
(ViPS)
11. Herpes zoster Live Live attenuated ND Varies with age; 51% Herpes Zoster ~5 years Efficacy is higher and wanes less for hospitalization for HZ and
attenuated (CD+ T cells overall; 69.8% in 50– Herpes Zoster post-herpetic neuralgia than for Herpes Zoster and Herpes
Vaccine Protective) 59 year ag group and ophthamicus Zoster ophthalmicus
18% in >80 years Post herpetic
neuralgia
12. Rotavirus vaccines Live attenuated oral vaccine ND 77% − 90% in developed, Rotavirus diarrhea 1–2 years Vaccine efficacy is lower and wanes more rapidly in high-mortality
(Secretary IgA) industrialized countries settings than in low-mortality settings
51% in developing
countries
13. Influenza vaccines- Inactivated split & sub-unit HI Abs: 1/40=50% 59% (95%CI: 41–71%) Influenza disease 6 months There is marked variation in the VE of different influenza sub-
Inactivated vaccines protection types. The decline in VE is more pronounced for A H3 than AH1
(1/320 in children) viruses.
*
14. SARS-CoV2 vaccine mRNA vaccine (mRNA-1273 ND 94.1% (95%CI: 89.3–96.8% Covid-19 3–6 months Duration of protection varies according to the severity of the
vaccine) (NAbs seems symptomatic disease, type of circulating variant, highest for the WT and
protective) disease lowest for Omicron and later sub-lineages
ND= Not Determined.
HI=hemagglutination inhibition (HI).
*The immune response to influenza is multifaceted and there are probably multiple correlates of protection.
EXPERT REVIEW OF VACCINES
393
394 V. M. VASHISHTHA AND P. KUMAR

Table 2. Factors determining durability of protective immunity.

Parameters Long durability Short durability
Antigen/Vaccine related factors
Antigen form Particulate antigens (virus particles or aggregated proteins) Homologous monomeric/soluble antigens
Antigen type T-cell dependent (Protein) T-cell independent (polysaccharide)
Antigen valence High Low
Adjuvant/s Addition of depot or slow-release formulations Non-adjuvanted inactivated vaccines
presence &
type
Antigenic Low High
diversity
Vaccine platform Live attenuated (replicating antigen), Virus like particle (VLP) All other platforms (Non-replicating antigens)
Antigen dose Higher Lower
Vaccination At least 4–8 weeks between priming doses and 6 months interval between Schedules with shorter interval
schedule primary doses and booster
Route of Intradermal/subcutaneous administration and heterologous prime-boost Homologous, conventional routes of administration
administration routes may facilitate longevity of immunity
Vaccinee related factors
Age at Older children and adults Extremes of age
vaccination
Gender Female gender Male gender
Genetic factors HLA Class II Polymorphism and individual HLA genotype may affect immunity HLA Class II Polymorphism may have a negative impact on
immunity
Gut microbiome Individual’s baseline gut microbiome composition and gut metabolome may Individual’s baseline gut microbiome composition and gut
positively impact immunity metabolome may have negative impact on immunity
Target pathogen and disease related factors
Incubation period Long Short
Force of infection Lower High
Site of infection Systemic infection Mucosal infection
Clinical endpoint Protection against severe disease Protection against infection

2.2.6. Diphtheria have demonstrated a waning in immunity after a single dose of

Protective levels of diphtheria antibodies (0.1IU/mL) persist for
decades after vaccination, although they wane in a section of
vaccinees after ten years [31]. The half-life of diphtheria-specific
antibodies is estimated to be around 19 years [32]. Considering
this and the fact that diphtheria infection has a short incubation
period, and the natural boosting is also limited with high vacci­
nation coverage, its booster is recommended every ten years,
especially in industrialized countries, to maintain protective
levels. However, recent studies have suggested that the protec­
tive titers persist much longer in the majority, and less frequent
boosters should be sufficient [33].
2.2.7. Tetanus
The duration of protection accorded by the tetanus vaccine is also
similar to the diphtheria antigen. The protective level of 0.1 IU/ml
of anti-tetanus antibodies persists for 3–5 years after the primary
schedule of 3 doses. Then, it may persist lifelong after boosters in
the second and fifth years of life and another during the adoles­
cent age in some people [33]. The half-life of tetanus-specific
antibodies is estimated to be around 11 years [31]. However, in
most persons, the level approaches minimal protective levels ten
years after the last dose [34]. Thus, its booster is recommended
every ten years to maintain protective levels. Recent studies have
indicated that less frequent boosting might be enough [35].
2.2.8. Varicella zoster vaccine
Many studies from the U.S.A. and Japan demonstrated the long-
term persistence of anti-varicella antibodies after a single dose
of varicella vaccine [36]. However, there are concerns that these
studies were conducted when the virus had a substantial circu­
lation in the community, and there may be some waning now
due to the absence of widespread transmission. Later studies
the OKA-strain varicella vaccine [37]. Though anti-varicella anti­
bodies are estimated to have a half-life of 50 years, there are
frequent fluctuations in the titers.
2.2.9. Mumps vaccines
Although wild mumps virus infection provides lifelong immu­
nity, recurrences of mumps disease are reported [38]. There
are at least 13 different strains of Mumps virus employed in
live attenuated vaccines [39]. They differ in efficacy to a certain
extent, but overall, they protect 80% of the recipients.
Some studies have reported 60–90% effectiveness after
a single dose [39]. According to a Cochrane review of 64 MMR
vaccine studies, one dose’s effectiveness was 69%-81% [40].
Another study finds that mumps-specific antibody titers per­
sist for at least 32 months after vaccination and slowly wane off. It
is estimated that 85% protection is there 6–7 years after two
doses of the vaccine [41] and decreases to pre-vaccination level
by 12 years without natural boosting [42]. The antibody titers
persist longer with natural boosting: for example, a study from
Finland reported 74% seropositivity 20 years after MMR vaccina­
tion [43]. A longitudinal study estimated the half-life of anti-
mumps antibodies to more than 500 years (95% CI: 90 to infinity)
and showed no significant decrease in titers over time [3].
2.2.10. Pneumococcal conjugate vaccines (PCVs)
Though the exact duration of protection has yet to be
established, PCVs provide reasonably good protection fol­
lowing a primary infantile schedule [44]. There are few long­
itudinal studies to measure persistent immunity against
pneumococcal diseases. Different experts have observed
a marked variation in the protection rate of different sero­
types. A study with PCV7 on nasopharyngeal carriage

noticed sustained protection for five years [45]. In South
Africa, an experimental PCV, PCV9, showed consistent pro­
tection for 6.3 years after vaccination against Invasive
Pneumococcal Disease (IPD) [46].
2.2.11. Rabies vaccine
Vaccine-induced neutralizing antibody (VNA) after rabies vacci­
nation is considered to be a valuable correlate of protection
against rabies, and a titer of ≥ 0.5 IU is taken as a cutoff [47].
Briggs et al. found that 80% of vaccinated subjects still had
detectable VNA titer after nine years [47]. Significantly, they did
not find any correlation between the VNA titer and the number
of vaccine doses received as a part of PrEP or PEP or the time
elapsed since the last dose of the vaccine series. However, the
intramuscular (IM) schedule induced neutralizing antibodies for
a longer duration than the intradermal schedule [48]. A German
study of the longevity of vaccination-induced rabies VNA found
detectable antibodies in 18 subjects 14 years after their last dose
in the Pr-EP and PEP schedules [49]. Furthermore, rabies vaccine
induced a robust immune memory that provides excellent
‘immune recall’ even after several years of primary schedule [50].
2.2.12. Herpes zoster recombinant vaccine
This new zoster vaccine is based on glycoprotein E of the
varicella-zoster virus (VZV) and has an AS01B adjuvant system.
The persistence of humoral immune response [anti-
Glycoprotein E (gE) antibodies] and cellular immune response
(gE-specific CD4+ T-cells) till six years after two doses of the
vaccine has been demonstrated [51]. Boutry et al. followed up
with 7413 participants enrolled in the long-term follow-up
study of the previous clinical trials to study the durability of
vaccine efficacy. They found 84.1% efficacy after eight years of
the second dose [52].
2.2.13. Whole cell pertussis (wP)
Various studies have estimated the duration of protection
offered by whole-cell pertussis (wP) vaccines, which ranges
from 4 to 12 years [53]. Long-term studies have shown
a definite waning of protection after wP vaccines and natural
infection over this period [53–55]. A study by Campbell et al.
from the UK cited 83.7% efficacy in children 10–16 years of age
following three primary doses, though a decline in vaccine
efficacy was noticed within 1–2 years of the third dose [56].
According to a systematic review, annual loss in the efficacy of
wP vaccines ranges from 2–13% [57].
2.2.14. Pneumococcal polysaccharide vaccine (PPSV)
Pneumococcal polysaccharide vaccine is recommended in older
adults and children with specific risk factors. On vaccination, the
antibody levels decline over time after an initial rise and reach
almost baseline levels within 4–7 years of vaccination [58].
Extensive studies in older adults have shown vaccine effective­
ness wanes over time, and effectiveness may be absent after five
years. However, a large cohort study, mainly in adults over 65,
has shown good protection against severe pneumococcal infec­
tions even after nine years [59].
EXPERT REVIEW OF VACCINES 395
2.2.15. Haemophilus influenzae type b (hib) conjugate
vaccine
Haemophilus influenzae type b (Hib) conjugate vaccine is
highly immunogenic with an estimated efficacy of 95–100%
after primary series [60]. Most experts believe that Hib con­
jugate vaccine provides a long-lasting immunity despite
waning in titers [61]. However, no exact duration of protec­
tive immunity is known, and the need for a booster dose
following the primary schedule is still uncertain [62]. It is
generally believed that the Hib conjugate vaccine protects at
least for five years after completion of the primary series.
Many countries have successfully controlled the Hib disease
with a three-dose primary schedule, but some countries had
to introduce a booster dose after a few years [62,63]. As per
some studies, the protection offered by three doses in
infancy lasts only till 2nd year of life and wanes quickly
[64,65]. The anamnestic response to booster dose is excel­
lent [64].
2.3. Vaccines that provide short duration of protection
(<5 years)
2.3.1. Meningococcal vaccines
Meningococcal polysaccharide vaccines, being T-cell indepen­
dent vaccines, do not provide durable protection/memory-cell
response. In younger children, 2–4 years of age, the protection
lasts only a few months, while in older children, it lasts 2–3
years. Revaccination again protects for a similar duration
[66,67].
Meningococcal conjugate vaccines offer better protection
than polysaccharide vaccines, but even with these, the effi­
cacy wanes over the years. The serological correlate of pro­
tection is serum bactericidal titer of ≥ 1:8 using baby rabbit
complement (rSBA) [68,69]. Immunogenicity study in children
aged 7–9 years has shown that seropositivity rates fall from
97.3% to 63.6% for serogroup A and 87.9% for other ser­
ogroups (C, W, and Y135) 2 years after vaccination and that
falls to a mere 20% after six years [70]. Cohn et al. have
shown that the vaccine efficacy of a single dose falls from
79% (49% to 91%) at <1 year post-vaccination to 61% (25%
to 79%) at 3 to <8 years post-vaccination [71]. The waning in
the protective antibody titers following meningococcal con­
jugate vaccines also varies with the child’s age, with waning
faster in kids under five years of age than kids above five
years of age [70].
2.3.2. Acellular pertussis (aP) vaccines
Compared to wP vaccines, waning is faster with acellular
pertussis (aP) vaccines. Schwartz et al. observed that the dura­
tion of protection following aP vaccines declined rapidly fol­
lowing four years of vaccination despite high early
effectiveness [72]. The efficacy drops from around 90% in the
first year after the last dose of the aP vaccine to 30–40% 6–8
years after the last dose [73–76]. Waning of protection after
TdaP vaccines is even faster: some studies have shown the
protection wanes quickly, with efficacy dropping to as low as
8.9% after four years [77–80].
396 V. M. VASHISHTHA AND P. KUMAR
2.3.3. Dengue vaccines
Currently, two live attenuated dengue vaccines – CYD-TDV
(Dengvaxia™ by Sanofi) and TAK-003 (Qdenga™ by Takeda)
are licensed and approved for use in different populations in
some countries. According to data from three efficacy trials,
CYD-TDV offers protection for five years against severe dengue
among seropositive individuals [81]. Another live dengue vac­
cine, TAK-003, has been evaluated for 54 months. The pub­
lished data showed a 62.0% efficacy against virologically
confirmed dengue (VCD) and 83.6% against hospitalized VCD
[82]. According to unpublished follow-up data, the vaccine
offered 64.2% vaccine efficacy against VCD in seropositive
individuals and 53.5% VE in seronegative individuals after 54
months. The vaccine efficacy against hospitalized dengue was
more than 80% after 54 months of follow-up [83].
2.3.4. Cholera vaccines
Two types of cholera vaccines are available globally: monova­
lent and bi-valent-killed whole-cell oral cholera vaccines. While
the prototype of the former is WC-rBS (recombinant B subunit
of cholera toxin – Dukoral®), there are three different bi-valent
vaccine products available globally that contain O1 and O139
strains (without the B subunit) and marketed as Shanchol™,
Euvichol™ and mORCVAX™ All of them, barring mORCVAX™
(mainly used in Vietnam), are WHO-Pre-qualified [84].
The estimated duration of protection of these cholera vac­
cines ranges from 6 months to 5 years. For the monovalent
Dukoral™ vaccine, the protection lasts only six months for
children and two years for adults. For the bivalent, whole-cell
vaccine, Shanchol™, protection lasts up to 5 years after vacci­
nation. In a large RCT conducted in Kolkata, the efficacy dif­
fered in different age groups – highest in older children and
adults and lowest in young kids. The combined VE after five
years was estimated to be 65% [85].
2.3.5. Japanese encephalitis vaccines
Japanese encephalitis vaccine-live (SA-14-14-2): Studies from
Nepal show that this live attenuated JE vaccine based on the
SA-14-14-2 strain provides reasonably good protection for five
years after a single dose. A case-control study in Nepalese chil­
dren found 96.2% effectiveness after five years of a single dose
[86]. Another case-control study among adults finds 77.0% (95%
CI: 67.0–83.0) effectiveness after seven years of a single dose
administration in two districts of Assam, India [87]. However,
a recent cross-sectional study conducted in the Gorakhpur dis­
trict of India finds that 97.74% of samples were negative for anti-
JEV-specific IgG antibodies after two years of the second vaccine
dose [88].
Inactivated Vero cell-derived vaccines (IXIARO®/JESPECT®
(Valneva, Austria) & JEEV®(BE, India): Data on the long-term
protection against the clinical disease from the endemic
region is limited. A Philippine study with IXIARO® among
300 children finds that 90% of un-boosted subjects had pro­
tective anti-JE antibodies after three years of primary vaccina­
tion of two doses [89]. A 5-year follow-up study among two-
dose recipients of the IXIARO vaccine in Austria finds that 81%
of the subjects retained the protective antibody titers [90].
Another study from the non-endemic region demonstrated
the persistence of sero-protection for six years after two pri­
mary doses of IXIARO and a booster dose after 15 months [91].
2.3.6. Typhoid vaccines
Vi-polysaccharide vaccine: A T-cell independent antigen, it
does not induce memory cells and immunoglobulin class
switching. Hence, it does not offer long-term protection and
requires revaccination every three years for continued pro­
tection [92]. Even within the three years, vaccine efficacy
falls from 64% after 21 months to ~ 55% in the
third year [93].
Typhoid conjugate vaccines: Conjugate vaccines, being
T-cell dependent, induce robust immune response with the
production of memory cells, thus offering long-term protec­
tion. One study conducted with the vaccine developed with
a nontoxic recombinant protein that is antigenically identical
to Pseudomonas aeruginosa (Vi-rEPA conjugate vaccine)
among two to five-year-old Vietnamese children demon­
strated 89% efficacy after 27 weeks of active surveillance fol­
lowed by 19 weeks of passive surveillance [94]. Studies
performed on another conjugate vaccine using tetanus toxoid
as a carrier protein, Vi-TT (Typbar-TCV™), demonstrated that
protection following a single dose might persist for up to five
years [95,96]. A longitudinal study finds the persistence of
anti-Vi-IgG antibodies up to 7 years following primary vaccina­
tion of children in both boosted and un-boosted cohorts.
However, there was a significant waning in the titers after
five years, and the manufacturer recommended a booster
after five years of the primary dose [96].
2.3.7. Herpes zoster live attenuated vaccine
This live attenuated vaccine gives protection for a shorter
duration than the recombinant, inactivated vaccine. Efficacy
against Herpes zoster and post-herpetic neuralgia hospitaliza­
tion is higher and better maintained. A real-world effective­
ness study demonstrated that herpes zoster vaccine efficiency
decreased from 67% (95% CI: 65% to 69%) in the first year to
15% (5% to 24%) after ten years [97]. Efficacy against post-
herpetic neuralgia dropped from 83% (78% to 87%) to 41%
(17% to 59%) during the same period. Vaccine efficacy against
herpes zoster ophthalmicus decreased from 71% (63% to 76%)
to 29% (18% to 39%), while that against herpes zoster hospi­
talization dropped from 90% (67% to 97%) to 53% (25% to
70%) in five to eight years [97].
2.3.8. Rotavirus vaccines
Vaccine effectiveness of live attenuated rotavirus vaccines
declines more rapidly in regions with high burden-high mortality
than in industrialized countries having low burden-low morbidity
[98]. According to a meta-regression study, the efficacy of live
oral rotavirus vaccines waned more rapidly in high-mortality
settings, and pooled efficacy after 12 months was only 44%. In
contrast, in low and middle mortality settings, the corresponding
figure was 77%–94% [99]. Some efficacy studies from the low
burden-low low mortality countries have demonstrated sus­
tained protection against severe rotavirus disease even after
three years of primary vaccination [100,101].

2.3.9. Influenza vaccines
Vaccines against influenza do not produce long-term protec­
tion. After immunization, the anti-HA antibodies peak 2–4
weeks after vaccination in primed individuals, whereas in
unprimed individuals and older adults, they peak ≥4 weeks
after vaccination. After six months, the titers drop by more
than 50%, with the amount of the drop proportional to the
highest titers attained. The titers then stay constant for two to
three years [102]. According to clinical trial data, immunity
against antigenically identical strains to those in the vaccina­
tion lasts for roughly 6–8 months [103].
The vaccine effectiveness (VE) of the various influenza sub­
types varies significantly. AH3 viruses have a more marked
decrease in VE than AH1 viruses. Moreover, the VE is influ­
enced by the interval since immunization. According to
a comprehensive review and meta-analysis, VE for influenza
virus subtypes A/H3 and type B is significantly less at 3–6
months after vaccination than 0–3 months after vaccina­
tion [104].
A different study discovered that the influenza A(H3N2),
influenza B, and influenza A(H1N1) pdm09 viruses caused
a 7% (absolute) monthly drop in VE. Patients who had
received influenza vaccinations in the previous season showed
a more marked decline in VE [105]. An Australian study dis­
covered an intra-seasonal drop in influenza vaccine effective­
ness. The study found that the best defense against influenza
verified in a lab was when immunization was given within two
months of the onset of symptoms [106]. Vaccine effectiveness
could disappear as soon as 90 days after inoculation, as per
a 2018 analysis of 11 recent studies on the vaccine’s durabil­
ity [107].
2.3.10. SARS-CoV-2 vaccines
There is no known broad estimate of the duration of protec­
tion offered by the SARS-CoV-2 vaccines against COVID-19
disease, which varies according not only to the disease state
and type but also to the circulating variants. Further, despite
the extensive use of different vaccines and hundreds of stu­
dies over three years, no reliable immune correlate of protec­
tion against the disease could be ascertained so far. Overall,
neither the infection nor the vaccines provide lasting protec­
tion. The effectiveness of these vaccines rapidly wanes over
time after primary and booster vaccination. Most studies,
including systematic reviews, found that protection waned
significantly within 3–6 months of a vaccine dose, especially
against the Omicron variant.
An extensive review evaluated 78 studies on vaccine-
specific vaccine efficacy/effectiveness of four COVID-19 vac­
cines before the advent of the Omicron variant concluded that
VE against symptomatic disease waned by 20–30% by six
months of the primary series. However, the VE remained
high, around 70% against severe disease, and declined only
10% after six months [108].
Another review based on 40 peer-reviewed studies finds
that the VE against the omicron variant was only 20% after six
months of the primary series and 30% after nine months of
a booster dose – a faster waning of VE noted against the
Omicron than the Delta variant [109].
EXPERT REVIEW OF VACCINES 397
Another review based on 41 studies on the performance of
exclusively inactivated COVID-19 vaccines found that primary
VE had waned significantly after six months [110]. The study
noted VE of 52.8% against the Delta variant, which went down
sharply against the Omicron (16.4%). However, like mRNA
vaccines, the VE against severe disease remained good even
after six months of primary series, which improved after
a booster dose [110].
3. Immunological basis of long-term protection
conferred by vaccines
Vaccines induce immune responses that are highly complex
and include orchestrated actions of a wide range of immune
cells in both innate and adaptive immune systems (Figure 1).
Ultimately, with most current vaccines, protection is provided
through pathogen-specific antibodies, which target specific
epitopes in pathogens or their toxic components. Antibodies
are exclusively produced by a subset of B-lymphocytes
(B-cells) called plasma cells. The process of antibody produc­
tion begins with the vaccine antigens reaching the draining
lymph nodes from the injection site, where they are captured
by specialized macrophages in the sub-capsular region and
then transported to B- -cell zone (follicles) (step ‘a’ in Figure 1).
Here, B-cells are activated, and activated B cells migrate
toward the border region between B-cell follicles and the
T-cell zone (called marginal zone) [111].
After that, there are two pathways: One, activated B-cells
can induce extra-follicular response (without any help from
T-cells), which leads to the production of short-lived plasma
cells (step ‘b’ in Figure-1). Bacterial antigens like lipopolysac­
charides induce this type of response. As the name suggests,
these short-lived plasma cells secrete antibodies for a short
time; thus, the vaccine-induced protection is only short dura­
tion. Without T-cell help, the antibodies produced are of low
to modest affinity and mostly IgM type with no isotype switch­
ing [111]. Of note, this reaction is relatively rapid, leading to
the appearance of IgM antibodies within a few days of vacci­
nation. Vi Polysaccharide typhoid vaccine is a classic example
of this [112].
The second pathway is the germinal center (GC) response
induction. This pathway involves intricately coordinated activ­
ities in different lymph node zones and is relatively slower: it
takes roughly two weeks for the germinal centers to develop
[113]. In the T-cell zone, the antigen is presented by major
histocompatibility complex (MHC) class II of antigen-
presenting cells (APC) like dendritic cells (DC) to naïve CD4+
T cells, leading to their functional differentiation to helper
T cells (Th cells) (step ‘c’ in Figure-1). These Th cells provide
helper signals to activate B-cells in the marginal zone to lead
to extra-follicular response, producing short-lived plasma cells
(step ‘d’ in Figure 1). These short-lasting plasma cells start
dying after some time, resulting in reduced antibody titers
noted 4–8 weeks after vaccination [114]. However, because
T-cells help in the form of type-1 cytokine interferon-gamma
(IFN-γ) (produced by follicular helper T-cells (TFH cells) and
Th1 cells) or Type 2 cytokines interleukin-4 (IL-4) [produced by
TFH and Th2 cells], there is isotype switching to IgG1/IgG3 or
IgG1 and IgE respectively. Some primed CD4+T-cells are
398 V. M. VASHISHTHA AND P. KUMAR
Figure 1. Schematic representation of vaccine-induced immune responses in the draining lymph node.
(Adapted from: Chen Z, Gao X, Yu D. Longevity of vaccine protection: Immunological mechanism, assessment methods, and improving strategy. View, 2022; 3,
20200103).
committed to differentiation toward TFH cells (step ‘e’ in
Figure 1), and they support the initiation and maintenance
of GC reaction [114,115].
The GC reaction is initiated by the migration of some
activated B cells toward germinal centers on getting signals
from primed T-cells and follicular dendritic cells (FDCs) (step ‘f’
in Figure 1). The FDCs are essential here: they attract antigen-
specific B and TFH cells and capture/retain antigens for
extended periods. B cells attracted by antigen-bearing FDCs
become the founders of the GC reaction. Each GC contains
B-cells of a single antigen only. These B-cells undergo massive
clonal proliferation, somatic hypermutation, and affinity
maturation [selection of fittest B-cells (with highest affinity)
after several ‘rounds’ of selection].
Moreover, they differentiate into long-lasting plasma cells
(step ‘g’ in Figure 1) that secrete large amounts of high-affinity
antibodies for extended periods (primary immune response)
[115]. Some GC B-cells differentiate into memory B cells (step
‘h’ in Figure 1). Memory cells persist as resting cells until re-
exposed to the same antigen when they re-proliferate and
differentiate into plasma cells, secreting large amounts of
high-affinity antibodies (secondary immune response) [115].
The decline of antibody titers after this secondary immune
response is much slower than that of the primary immune
response. Thus, a rapid increase in antibody titer is noted
within days of infection with the same pathogen later or
after a booster dose of the vaccine. During the GC reaction,
a fraction of plasma cells can migrate toward long-term survi­
val niches mainly located within the bone marrow, where their
survival and antibody production may persist for years [116].
The long persistence of antibodies can be predicted by mea­
suring antibody titers between 6–12 months of vaccination, as
by this time, all short-term plasma cells have disappeared, and
in the absence of repeat vaccination, the antibodies in serum
are those secreted by long-lasting plasma cells only [117].
In addition to this antibody-mediated immune response
(humoral immune response), CD8+ T cell-mediated cytolysis
is a crucial mechanism of cellular immunity against intracellu­
lar infections. It is induced in the T-cell zone where naïve CD8+
T-cells are activated by cross-presentation of the antigen via
 EXPERT REVIEW OF VACCINES 399

the MHC class I molecules on dendritic cells that drive their
differentiation into short-lived effector CD8+ T-cells (step ‘i’ in
Figure 1) or resident memory CD8+ T-cells (step ‘j’ in Figure 1)
[118]. Like a humoral immune response, most short-lived
cytotoxic effector cells enter programmed cell death at the
end of primary immune responses. In contrast, memory CD8+
T cells persist over a more extended period, and they can
rapidly proliferate into a massive wave of effector cells upon
re-exposure to the same pathogen. In addition to protecting
intracellular antigens, the memory function of CD8+ T cells has
been suggested to be a significant protection mechanism for
the elderly with inadequate antibody responses [114].
Moreover, a new subset of CD8+ T cells that persist in non-
lymphoid tissues for an extended period and can control
reinfection has been recently identified. Termed tissue-
resident memory T cells (TRM) they are of great interest for
developing vaccines against infections entering through
respiratory and digestive tracts where conventional antibody-
based vaccinations cannot induce sufficient capacity to neu­
tralize pathogens during initial infections [119].
The critical determinants of the persistence of humoral
immunity are two broad immune mechanisms – memory
B-cell dependent and memory B-cell independent. The immu­
nity in the latter is provided through antibodies produced by
the long-lived plasma cells residing in the bone marrow niches
[120]. The memory B-cells themselves do not provide protec­
tion, but they divide and differentiate into plasma cells after
antigenic exposure to secrete large amounts of antigen-
specific antibodies [3]. So, to assess the longevity of immunity
induced by an immunogen, measuring the memory B-cell
counts should provide an estimate of the durability of immu­
nity. However, studies have shown that this correlation does
not exist for all vaccines in real life. While in the case of
specific antigens like measles and rubella, the memory B-cell
population remains stable and correlates well with antibody
levels decades later, whereas, in the case of some other anti­
gens like varicella – zoster virus, Epstein – Barr virus, tetanus,
or diphtheria, no such correlation exists [3]. It is also noticed
that this association fails to exist for those vaccines requiring
multiple or repeated doses. This observation reflects that the
mere persistence of memory B-cells may not guarantee the
durability of antibodies, and some other mechanism may be
involved in maintaining the long-term antibody levels. One
such mechanism could be ‘imprinted lifespan’ phenomenon in
which B-cell signaling during the induction of antigen-specific
immune response determines the life span of the plasma cells
[121]. Most antigens induce memory B-cell formation, but the
duration of antibody production is not the same. This hypoth­
esis may explain why certain antigens provide long-term
immunity while others provide only short-term protection.
During the process, the exact mechanisms responsible for
differentiating immune cells toward different subsets and
pathways are also poorly understood even today. However,
the induction of good GC reactions, many long-lasting plasma
cells, and the formation of memory B-cells and T-cells are
essential for durable, long-lasting vaccine-induced protection
[115] (Figure 2).
4. Determinants of the longevity of antibody
response
Certain known factors determine how long the vaccine-
induced antibody responses can be expected to last (Table 2):

B-Cells
Spleen

c . Long lived plasma cells

b. Memory B cells
a . Germinal centers in a lymph node

T-Cells

Thymus

d. Memory T cells
e. Tissue resident memory T cells

Figure 2. Key immunological determinants of durable vaccine-induced immune responses.

Both B-cell and T-cell responses help in providing durability to vaccine-induced immune responses. A. Germinal centers (encircled) in lymph nodes are factories of
B-cell production and their maturation. B. Memory B cells in lymphoid tissues like the spleen. C. Long-lived plasma cells move to the bone marrow niches and
survive there, providing long-lasting immunity.
D. Memory T-cells in the lamina propria and epithelium of the intestine. E. Tissue-resident memory T-cells (TRM) in the nasal passages and lungs. These cells are in
non-lymphoid tissues, such as skin, gut, and lung airways, and do not recirculate through the blood. Most T cells mature in the thymus gland before subsequent
export to the periphery.
400 V. M. VASHISHTHA AND P. KUMAR

4.1. Vaccine- and vaccination-related factors this principle. For instance, the recently approved RTS,
S vaccine for malaria consists of a repeating, particulate anti­
4.1.1. Vaccine platform
gen combined with a potent adjuvant [127]. Nevertheless, this
The vaccine platform is crucial to determining longevity.
vaccine induces a protective immune response only in around
Among all vaccination platforms, only live-attenuated and
36% of individuals at vaccination, and the level of protection
virus-like particle (VLP)-based vaccines elicit long-lasting
diminishes to 0% over three years [128].
antibody responses that can endure for several decades,
Another recent development in vaccinology is the ‘struc­
or even a lifetime, without the need for further exposure
ture-based’ design of protein antigens (now termed ‘designer
to the antigen or reactivation of immunological memory.
antigens’), which delineate the antigenic structures in the ‘pre-
Amanna et al. conducted a long-term study on the levels of
fusion’ and ‘post-fusion’ forms. The advent of new imaging
specific antibodies against viral antigens (vaccinia, measles,
techniques like X-ray crystallography and cryogenic electron
mumps, rubella, varicella-zoster virus, and Epstein-Barr
microscopy (Cryo-EM) has made it possible to study these
virus) and non-replicating antigens (tetanus and diphtheria)
forms. Antibodies directed against the ‘post-fusion’ (after the
in 45 individuals over up to 26 years. They discovered that
antigen fuses with the host cell) shape do not thoroughly
the antibody responses against the viruses remained
neutralize the circulating form of the virus before it binds to
remarkably stable, with estimated half-lives ranging from
cells, known as the ‘prefusion’ form. Antibodies directed
50 years for the varicella-zoster virus to over 200 years for
against the epitopes, exposed during only the pre-fusion
other viruses like measles and mumps [3]. The antibody
form, are highly potent in neutralizing the virus. The knowl­
responses to non-replicating antigens (tetanus and
edge about this concept led to the successful development of
diphtheria) declined faster, with estimated half-lives of 11
respiratory syncytial virus (RSV) vaccines and has also been
years and 19 years, respectively [3,121]. Live vaccinations, in
employed in designing a few mRNA and protein-based COVID-
contrast to non-live antigens, cause activation of several
19 vaccines [129].
lymph nodes due to the multiplication and spread of
microbes [117]. The process of microbial replication leads
(1) Antigen type is a crucial determinant of the longevity of
to a constant production of antigens, which in turn con­
immune responses elicited by a vaccine. Polysaccharide
tributes to an intense and persistent immune response.
antigens are ‘T-cell independent’ and do not induce
VLP-based vaccines, such as the Human Papilloma Virus
TFH cells and GC reaction in the absence of T-cell
(HPV) vaccine, consist of supramolecular nanoparticles with
help (vide supra) [117]. Thus, the antibody response to
highly repetitive antigen sequences displayed on their sur­
these antigens is predominantly IgM type, low titers of
faces. The high antigen valency of VLPs, which refers to
low-affinity IgG, and only of short-duration [117].
how densely the vaccine antigen is presented to the
Hence, the antibody response’s durability and ‘quality’
immune system, can significantly enhance early B-cell acti­
are suboptimal. Conjugation of polysaccharide antigen
vation and the persistence of GC responses. This, in turn,
to a ‘carrier’ protein can lead to induction of TFH cells,
leads to increased, long-lasting plasma cell differentiation
GC reaction, and thus high-affinity antibody response
and thus results in a durable and long-standing immune
with isotype switching and immune memory, leading
response [122].
to longer-term protection, as seen with Pneumococcal
COVID-19 vaccines are attractive, as multiple vaccines have
conjugate and typhoid conjugate vaccines [130].
been developed, primarily based on its spike antigen, but on
(2) Adjuvants. Adjuvants improve the immune response to
different platforms [123]. For example, Moderna’s mRNA vac­
inactivated vaccines in many ways, such as modifying
cine induces high titers of vaccine-induced binding and neu­
how the antigen is delivered, how long it persists (using
tralizing antibodies and CD4 and CD8 cells. However, these
depot or slow-release formulations), and boosting Th
wane off by six months, while Janssen’s vaccine, which is
responses (immunomodulation) [131]. Adjuvants can
a virus vector (Adenovirus-26) based vaccine, induces anti­
enhance the durability of vaccine-induced immunity
body titers, CD4 and CD8 cells that have lower peak than
by enhancing both the quality and intensity of immu­
mRNA vaccine, but persist longer (up to 8 months) [124].
nological responses.
Further, studies have shown that boosting with a vaccine
(3) Antigen dose is also a factor as far as the durability of
from a different platform (heterologous boosting) induces
vaccine-induced immunity is concerned. An increase in
a better immune response than a homologous schedule [125].
antigen dose, in general, enhances immune response
by increasing the availability of the antigen for B/T-cell
4.1.2. Antigen form binding. However, there is some complexity as the
The form of the antigen influences the immune response. antigen dose is also shown to impact the induction of
Particulate antigens, such as virus particles or aggregated T-regulatory cells (Tregs) apart from affecting Th1/Th2
proteins, stimulate more effective antigen uptake and migra­ bias and recruitment of Th17 and TFH cells [132].
tion by dendritic cells. They lead to more robust responses (4) The vaccination schedule also regulates the magnitude
from CD4+ and CD8+ T cells than when the antigen is mono­ and duration of the antibody response. When priming
meric or soluble [126]. Therefore, particle antigens and heat- doses are administered at intervals of less than one
or chemical-induced aggregated antigens elicit a more robust month, the resulting immune responses are less long-
and long-lasting immune response than soluble, monomeric lasting than when the same number of vaccine doses
antigens. Nevertheless, several practical instances deviate from are given at longer intervals (1-2 months). This is

because fewer post-GC B cells are generated, which are
capable of long-term survival. A shorter period between
waves of primary reactions increases competition,
negatively impacting durability. For the best memory
retrieval and enhanced immune responses, it is neces­
sary to have longer intervals of at least 3 to 4 months.
The optimal timing for a booster dosage is at least 4-6
months after the last priming dose, allowing for the
necessary affinity maturation of B-cells in the germinal
center and creating memory cells [117]. Administering
the booster dose ‘prematurely’ leads to elevated anti­
bodies at the boosting time, creating antigen-antibody
complexes, which diminishes the antigens available for
B-cell priming. Additionally, antibody-mediated feed­
back mechanisms may directly affect B cells negatively.
The optimal schedule for non-live T-cell dependent
immunizations that operate on the ‘prime-boost princi­
ple’ is ‘0, 1, 6 months’ [117].
(5) Route of administration. The immunological response to
a vaccine can differ depending on the route of admin­
istration. For instance, Styles et al. showed in their
animal study that intradermal vaccination led to better
antigen retention in the lymph nodes than intramuscu­
lar administration, which resulted in a more robust and
longer-lasting activation of antigen-specific GC T and
B cells [133]. Jegaskanda et al. showed that intranasal
live-attenuated influenza vaccine, followed by a booster
of intramuscular subunit vaccine, resulted in a robust
immune response [134]. Similarly, administering intra­
muscular mRNA-lipid nanoparticles as the initial dose,
followed by intranasal protein vaccine as a booster, led
to a strong and effective immune response against
SARS-CoV2 [124]. Hence, a combination of various plat­
forms and delivery methods can enhance the durability
of protection.
4.2. Vaccinee-related factors
Age at vaccination: The vaccinee’s age at the time of vaccina­
tion also affects vaccine antibody persistence, as the response
is shorter at both extremes of age because of immaturity and
senescence of the immune system, respectively [117]. In
infancy, the immune response to live attenuated vaccines is
also adversely affected by preexisting antibodies transferred
antenatally through the placenta [135]. Even immune
response to non-live vaccines is affected by these maternally-
derived antibodies but to a lesser extent.
Gender: Although this aspect is not yet well studied, some
indications indicate that immune response might also vary
with gender. Studies have demonstrated that females elicit
more exuberant immune responses to infections than males
[136,137].
Genetic factors: Antigen epitopes associated with many
MHC molecules are more likely to induce response. Gene
polymorphisms in critical molecules required for B and T cell
activation/differentiation molecules affect the quality of anti­
body responses. Individual and community variations of MHC
EXPERT REVIEW OF VACCINES 401
molecules [human leukocyte antigen A2 (HLA A2)] affect T-cell
responses significantly [138].
Disease conditions: Certain disease conditions also affect
vaccine antibody persistence. Increased catabolism (as in HIV)
or urinary or digestive tract antibody loss reduces vaccination
antibody persistence. Immunosuppressive medicines and con­
ditions impact the durability of vaccine-induced protection.
Recent studies suggest obesity may accelerate the waning of
COVID-19 and influenza vaccine efficacy [139].
Gut microbiome : Recent research reveals that the gut
microbiome impacts the development of the immune system
and immunological response to vaccines. The way by which
the establishment of gut microbiome at/after birth affects
childhood vaccination response is unknown [140,141].
4.3. Target-pathogen related factors
The target pathogen and its pathogenicity significantly
influence the immune response and longevity. For instance,
the incubation period and the force of infection transmis­
sion (the pace at which illness is acquired in a community)
impact the effectiveness of vaccines. A lengthier incubation
period allows for a more efficient memory response and
enhanced long-term protection against symptomatic illness
[124]. This phenomenon has been extensively documented
during the SARS-CoV-2 pandemic, wherein the level of pro­
tection against infection declined as the incubation periods
of new strains of SARS-CoV-2 reduced [142]. Moreover, it
has been found that the effectiveness of vaccines is gen­
erally greater in regions where viral transmission, or the
force of infection, is lower. This phenomenon was demon­
strated in the case of a pentavalent rotavirus vaccine, which
showed real-world efficiency ranging from 45% to 90%
[143]. OPV also exhibited significant variations in effective­
ness [144].
Licensed and experimental vaccines against viruses that
replicate on mucosal surfaces without causing systemic
infection/significant viremia also fail to induce durable pro­
tection. Natural infection with these viruses [like influenza,
parainfluenza, RSV, SARS-CoV2, and other ‘human common
cold viruses’] also does not provide long-term protection.
The possible factors include: (a) They do not come in con­
tact with multiple immune compartments and immune-
competent cells, unlike other viruses like measles, mumps,
rubella, smallpox, etc., (b) they have a shorter incubation
period, as they start causing illness just after mucosal repli­
cation (the time required for systemic spread after mucosal
replication is cut-off) [1]. Due to the shorter incubation
period, the immune system does not get adequate time
to mount an adequate/robust immune response; (c) the
half-life of nasal secretary IgA is much shorter than serum
IgG. Thus, the viruses that induce mainly mucosal immune
responses do not result in durable protection against these
viruses [145,146]. There is another explanation from an
evolutionary point of view: Unlike other immune compart­
ments, mucosal surfaces regularly come in contact with
a much larger number of antigens. Hence, they have
evolved to ‘tolerate’ less dangerous antigens and down-
regulate immune responses to them to minimize bystander
402 V. M. VASHISHTHA AND P. KUMAR
tissue damage, focussing on more dangerous antigens for
robust immune response. The mechanisms for this immune
‘decision-making’ have not been fully understood yet [1].
Viral genetic variability (number and variety of viral strains/
variants that are circulating) also affects vaccine efficacy
adversely, as is readily observed with influenza and SARS-
CoV2 viruses [147,148].
4.4. Other factors
Some other ‘environmental factors,’ largely unknown, might
also affect vaccine-induced immune response. For example,
there is a drastic difference in immune response to oral
polio vaccine (OPV) among tropical and temperate coun­
tries [144]. One hypothesis that explains this effect is that in
tropical countries, multiple enteric pathogens are in circula­
tion that affect the ‘uptake’ of the vaccine by the immune
system [149].
Even the time of day a vaccine is delivered has been shown
to affect immune response robustness. The effect of the circa­
dian clock on critical immune cell functions, including cytokine
production, cell trafficking, dendritic cell activity, and T and
B cell activity, has been shown; however, the exact mechanism
of its effect on the immune response at the cellular or mole­
cular level is still unclear [150,151].
5. How can we improve the durability of
vaccine-induced protection?
5.1. Challenges and the way ahead
Despite the vaccines’ 225-year success in controlling infectious
disease, improving quality of life, increasing life expectancy,
and generating substantial economic benefits, it is ironic that
we are still learning how the best vaccines work and how to
improve vaccine design to improve protective efficacy. Most of
the current vaccines have been empirically developed. Vaccine
durability assessment is also a ‘wait-and-see’ method due to
ignorance of immunological memory mechanisms and chal­
lenges in measuring cellular components that induce long-
lasting immune protection [152]. Recent advancements are
beginning to reduce our knowledge gaps in underlying
mechanisms of vaccine-mediated protection and long-term
immunity. We may induce more effective and long-lasting
immunity with fewer dosages by exploiting these nuances
and optimizing immune response linkages.
Natural infection-induced immunity is usually more persis­
tent than vaccine-induced protection. Exploring this disparity
is one approach to developing more durable protection vac­
cines. Beukema et al. [153] prolonged antigen delivery to
replicate natural infection antigen dynamics to improve influ­
enza vaccination durability in mice. They compared the
immune response to standard prime-boost immunization
with a 28-day interval to that of daily doses of whole-
inactivated influenza virus vaccine for 14, 21, or 28 days. The
28 days of extended antigen administration achieved the high­
est cellular and humoral immune response levels, followed by
21 and 14 days of delivery and prime-boost immunization
[153]. Prolonging vaccine delivery also improved the quality
of antibody response, as shown by significantly high levels of
high avidity, balanced IgG subclass, and cross-reactive antibo­
dies. Lee et al. found that long-prime, slow-delivery (12 days)
priming of HIV envelope protein immunogen in rhesus mon­
keys led to more memory B-cells, higher antibody somatic
hypermutation, and more robust immune responses to non-
immunodominant epitopes [154]. Further research is needed
to identify the optimal antigen delivery methods and formula­
tions that prolong antigen availability, elicit long-lasting and
protective immunity against influenza and other viruses, and
vaccines that provide long-term protection with fewer doses.
Phase 1 of the HIV vaccine clinical trial on this concept is
underway (NCT05471076) [124].
Unlike unadjuvanted platforms or those with a single adju­
vant, replicating viral vectors mimic natural infections and
activate several receptors and inflammatory pathways to sus­
tain immune responses. Therefore, early innate signals differ
by pathogen or platform and may be surrogate endpoints to
accelerate vaccine development and enable more durable
protection [124]. Immune correlates of protection by most
modern vaccines are antibodies against pathogen antigens
[155]. Since the cellular response is difficult to measure, we
have mainly focused on humoral antigen response. However,
the quantitative analysis and functional characterization of
CD4+ and CD8+ T-cell memory have advanced in the recent
2–3 decades. Multiple methods, such as MHC Class I tetramers,
peptide-induced intracellular cytokine labeling, and IFNγ
ELISPOT, can evaluate the frequency of antigen-specific T-cell
responses [156]. With advanced flow cytometry equipment
and reagents, many T-cell functions and phenotypic markers
can be evaluated simultaneously. These investigations and
advanced microarray analysis of T-cell gene expression profiles
have provided information on memory T-cell response [126].
For instance, antiviral T-cell memory lasts decades after small­
pox immunization [157,158] and SARS-CoV-1 infection [159].
Despite all the information and the growing consensus that
for the most challenging infectious diseases (e.g. AIDS,
malaria, and tuberculosis), a combination of effective patho­
gen-specific humoral and cell-mediated immunity may be
needed to create an effective vaccine, we are still far from
harnessing cellular immunity. Identification and validation of
T cell-specific correlates of immunity (or co-correlates of
immunity of T cells and antibodies needed for vaccine-
mediated protection) will go a long way in achieving tremen­
dous success in this field.
New adjuvants should also be explored to prolong vaccine-
induced protection. Inactivated and recombinant vaccines use
adjuvants to boost vaccine-mediated immune responses,
increasing seroconversion rates, antigen dose sparing, and
fewer doses for similar protection. Alum salts, the most pop­
ular adjuvants, face the same issues as vaccines: their mechan­
ism of action is still debated [160]. Newer adjuvant systems
may target innate immune system signaling pathways like
Toll-like receptors (TLR) to direct vaccination-induced immu­
nity and better match pathogen-specific immunity require­
ments (e.g. skewing of cellular vs. humoral immunity),
resulting in a longer-lasting immune response. For example,

AS04, a combination of MPL (monophosphoryl lipid A) (a TLR-
4 agonist) and aluminum hydroxide, is used in an HPV vaccine,
TCV™. This HPV vaccine Cervarix®, when compared to
Cervarix®, on the same vaccine platform (Virus-like Particle,
VLP) but with only an aluminum salt (aluminum hydroxy
phosphate sulfate) as adjuvant, induced a 2- to 9-fold greater
antibody response but had a similar serum-antibody decay
showing that ASO4 does not substantially change humoral
immune response kinetics [161]. Thus, a better adjuvant sys­
tem can help us achieve a ‘tailor-made’ immune response.
Given the theoretical possibility of immune-mediated disease
induction with such an adjuvant, caution is warranted toward
safety when pursuing this approach.
6. Conclusion
Vaccination research and development have made great
strides in the last two centuries, yet most vaccines have
been developed empirically. We must still understand their
mechanisms, especially the complicated interaction of
innate, humoral, and cellular components and their subcom­
ponents [162]. Discoveries in this field are beginning to
reduce our knowledge gaps. Similarly, bioengineering tech­
nologies are evolving rapidly. With nanoparticle and virus-
like particle vaccinations, antigen valence and density are
finely regulated. Antigen delivery can be controlled and
sustained via newer biomaterials. New adjuvants, especially
mucosal ones, can activate specific innate immune path­
ways. As the mechanisms of immune response durability
become clearer, we can construct vaccines strategically to
provide durable vaccine-induced protection with fewer
doses.
7. Expert opinion
Vaccines have contributed immensely to the reduction of
morbidity and mortality associated with infectious diseases,
and ultimately reduction in infant/under-five mortality rates,
Disability Life Years (DALY), school and work absenteeism, and
thus rise in productivity, the standard of living and life expec­
tancy, We have achieved a lot despite having only a handful of
vaccines that provide long term (>20 years/lifelong) protection
with one or two doses; vast majority of vaccines provide
protection for 7–10 years, and often require multiple doses.
Quite a few vaccines provide only short-term protection (<5
years). Enhancing longevity to the vaccine-induced protection
would undoubtedly act as a ‘force multiplier’ in achieving all
the benefits enumerated above. Further, by helping drastically
reduce the cost of immunization programs, it has tremendous
direct and indirect economic benefits to the nations, adding to
the reputation of vaccines in particular and medical science in
general.
The last few years have seen some rapid strides in the
development of vaccines. The gestation period of developing
a new vaccine has been cut down significantly – from the
approval of a concept to the licensing of a product. Thanks
mainly to the advent of new vaccine platforms, like nucleic
acid-based mRNA and DNA vaccines, coupled with the
advanced knowledge of biologically active forms of antigens
EXPERT REVIEW OF VACCINES 403
and their interaction with the host cell, helped experts to
design more effective and potent formulations, as shown in
the successful development of RSV vaccines. Some progress in
ensuring vaccine-induced immunity’s longevity is also there,
but it is much slower. As discussed in our review, HPV vaccines
shine out in this aspect. Based on the VLP vaccine platform,
they have supramolecular nanoparticles with highly repetitive
antigen sequences on their surfaces that significantly promote
the early B-cell activation and the persistence of GC responses,
leading to enhanced long-lasting plasma cell differentiation
and durable immune response. Thus, despite being inacti­
vated vaccines, they offer long-term protection, similar to
live attenuated vaccines, without needing boosters. Many
other strategies are currently being hotly researched to
improve the durability of vaccine protection. Tweaking con­
ventional immunization techniques such as long-prime, slow-
delivery (12 days) immunization approach is one such strategy
in this direction, as demonstrated in some animal studies with
experimental HIV vaccine [154] and influenza vaccine devel­
opment [153].
Most currently licensed vaccines have been developed
empirically with a ‘develop and then see/assess’ approach.
The need of the hour is to develop vaccines strategically.
Undoubtedly, there are challenges regarding our understand­
ing of immunology and the exact correlates of long-term
protection. Thus, there is a need to identify ‘protective thresh­
olds’ for different vaccine formulations and bio-markers of
protective immunity so that minimum antibody levels should
be maintained above the threshold to avoid a breakthrough
infection [107].
As elaborated in the review, the two vital immunological
mechanisms that enhance the persistence of immune
responses are memory B cell generations in the germinal
centers and the survival of long-lived plasma cells in the
bone marrow niches. There is a need to recognize factors
that lead to the genesis and persistence of germinal centers
apart from the nature and kinetics of their delivery.
Similarly, identifying early innate signals that differ by
agents and vaccine platforms could help develop and
ensure the survival of long-lasting plasma cells in the
bone marrow, providing a lasting immune response.
Working on adjuvanted SARS-CoV-2 vaccine on non-
human primates, Prabakaran et al. have demonstrated
a sensitive method to identify and isolate antigen-specific
long-lived plasma cells (LLPCs). Their published work has
shown that spike protein vaccination can elicit and maintain
LLPCs [163].
Targeting specific epitopes or genes in antigenic sites
conserved in different variants can also ensure the durabil­
ity of protection. Further, there is a need to focus beyond
the measurement of antibody production and target key
mucosal sites to demonstrate tissue-generated memory
cells at different mucosal tissues, which may help prevent
breakthrough infections and ensure longevity.
Identifying solutions to these gaps in our understanding
should form the future research agenda in the vaccinology
field. We are confident that we are moving slowly but surely
from an era of empirically developed vaccines to that of
‘designer vaccines,’ with particular emphasis on the durability
404 V. M. VASHISHTHA AND P. KUMAR
of protection. In the coming years, the vaccine industry shall
be able to resolve the current shortcomings with the help of
advancements in biomaterials and bio-engineering for vaccine
development.
Funding
This paper was not funded.
Declaration of interests
The authors have no relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manu­
script. This includes employment, consultancies, honoraria, stock own­
ership or options, expert testimony, grants or patents received or
pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Author contributions
VMV and PK have substantially contributed to the conception and
design of the review article and interpreting the relevant literature,
and been involved in writing the review article or revised it for intel­
lectual content.
ORCID
Vipin M. Vashishtha http://orcid.org/0000-0003-1097-117X
References
Papers of special note have been highlighted as either of interest (•)
or of considerable interest (••) to readers.
1. Morens DM, Taubenberger JK, Fauci AS. Rethinking next-generation
vaccines for coronaviruses, influenza viruses, and other respiratory
viruses. Cell Host Microbe. 2023;31(1):146–157.
• This article reviews the factors behind the differences of dur­
ability of protection offered by vaccines against the visruses
that cause systemic infection/viremia versus those that multi­
ply in mucosal surfaces only and don’t cause viremia.
2. Markowitz LE, Preblud SR, Fine PE, et al. Duration of live measles
vaccine-induced immunity. Pediatr Infect Dis J. 1990; 9(2): 101–110.
doi: 10.1097/00006454-199002000-00008
3. Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to
common viral and vaccine antigens. N Engl J Med. 2007;357
(19):1903–1915.
• This longitudinal analysis of antibody titers specific for viral
antigens and nonreplicating antigens for a period of up to 26
years gives deep insight into differences in kinetics of anti­
body titres of different types of antigens.
4. World Health Organization. Rubella vaccines: WHO position paper.
Wkly Epidemiol Rec. 2020;95:301–324.
5. Crooke SN, Riggenbach MM, Ovsyannikova IG, et al. Durability of
humoral immune responses to rubella following MMR vaccination.
Vaccine. 2020;38(51):8185–8193. doi: 10.1016/j.vaccine.2020.10.076
6. Poland JD, Calisher CH, Monath TP, et al. Persistence of neutralizing
antibody 30-35 years after immunization with 17D yellow fever
vaccine. Bull World Health Organ. 1981;59(6):895–900.
7. Reinhardt B, Jaspert R, Niedrig M, et al. Development of viremia
and humoral and cellular parameters of immune activation after
vaccination with yellow fever virus strain 17D: a model of human
flavivirus infection. J Med Virol. 1998;56(2):159–67. doi: 10.1002/
(SICI)1096-9071(199810)56:2<159:AID-JMV10>3.0.CO;2-B
8. Groot H, Riberiro RB. Neutralizing and haemagglutination-inhibiting
antibodies to yellow fever 17 years after vaccination with 17D vaccine.
Bull World Health Organ. 1962;27(6):699–707.
9. Niedrig M, Lademann M, Emmerich P, et al. Assessment of IgG
antibodies against yellow fever virus after vaccination with 17D
by different assays: neutralization test, haemagglutination inhibi­
tion test, immunofluorescence assay and ELISA. Trop Med
Int Health. 1999 Dec;4(12):867–71.
10. Coulange Bodilis H, Benabdelmoumen G, Gergely A, et al. Persistance
à long terme des anticorps neutralisants de la fièvre jaune chez les
personnes âgées de 60 ans et plus [Long term persistence of yellow
fever neutralising antibodies in elderly persons]. Bull Soc Pathol Exot.
2011;104(4):260–265. doi: 10.1007/s13149-011-0135-7
11. Marchesani R, Thomas N, Monath, et al. Comparative safety and
immunogenicity of two yellow fever 17D vaccines (ARILVAX and
YF-VAX) in a phase III multicenter, double-blind clinical trial. Am
J Trop Med Hyg. 2002;66(5):533–541. doi: 10.4269/ajtmh.2002.66.533
12. World Health Organization. WHO position paper on hepatitis
a vaccines – October 2022. Wkly Epidemiol Rec. 2022;97:493–512.
13. Espul C, Benedetti L, Cuello H, et al. Persistence of immunity from
1 year of age after one or two doses of hepatitis a vaccine given to
children in Argentina. Hepat Med. 2012;4:53–60. doi: 10.2147/
HMER.S33847
14. Urueña A, Badano MN, Baré P, et al. Humoral and cellular immune
memory response 12 years following single dose vaccination
against hepatitis a in Argentinian children. Vaccine. 2022;40
(1):114–121. doi: 10.1016/j.vaccine.2021.11.037
15. Bianchi FP, Larocca AMV, Bozzi A, et al. Long-term persistence of
poliovirus neutralizing antibodies in the era of polio elimination:
An Italian retrospective cohort study. Vaccine. 2021;39
(22):2989–2994. doi: 10.1016/j.vaccine.2021.04.005
16. World Health Organization. Polio vaccines: WHO position paper.
Weekly Epidemiol Rec. 2022;97:277–300.
17. Larocca AMV, Bianchi FP, Bozzi A, et al. Long-term immunogenicity
of inactivated and oral polio vaccines: an Italian retrospective
cohort study. Vaccines (Basel). 2022 17;10(8):1329. doi: 10.3390/
vaccines10081329
18. Bhave S, Sapru A, Bavdekar A, et al. Long term immunogenicity of
single dose of live attenuated hepatitis a vaccine in Indian children
- results of 15-year follow-up. Indian Pediatr. 2021;58(8):749–752.
doi: 10.1007/s13312-021-2285-4
19. Chen Y, Zhou CL, Zhang XJ, et al. Immune memory at 17-years of
follow-up of a single dose of live attenuated hepatitis a vaccine.
Vaccine. 2018;36(1):114–121. doi: 10.1016/j.vaccine.2017.11.036
20. Ott JJ, Irving G, Wiersma ST. Long-term protective effects of hepa­
titis a vaccines. A systematic review. Vaccine. 2012;31(1):3–11. doi:
10.1016/j.vaccine.2012.04.104
21. World Health Organization. Human papillomavirus vaccines: WHO
position paper (2022 update). Wkly Epidemiol Rec. 2022;97:645–672.
22. Porras C, Tsang SH, Herrero R, et al. Efficacy of the bivalent HPV
vaccine against HPV 16/18-associated precancer: long-term
follow-up results from the Costa Rica vaccine trial. Lancet Oncol.
2020;21(12):1643–1652. doi: 10.1016/S1470-2045(20)30524-6
23. Kjaer SK, Nygård M, Sundström K, et al. Final analysis of a 14-year
long-term follow-up study of the effectiveness and immunogeni­
city of the quadrivalent human papillomavirus vaccine in women
from four Nordic countries. E-Clin Med. 2020;23:100401. doi: 10.
1016/j.eclinm.2020.100401
24. Olsson SE, Restrepo JA, Reina JC, et al. Long-term immunogenicity,
effectiveness, and safety of nine-valent human papillomavirus vac­
cine in girls and boys 9 to 15 years of age: interim analysis after 8
years of follow-up. Papillomavirus Res. 2020;10:100203. doi: 10.
1016/j.pvr.2020.100203
25. Kjaer SK, Nygård M, Sundström K, et al. Long-term effectiveness of
the nine-valent human papillomavirus vaccine in Scandinavian
women: interim analysis after 8 years of follow-up. Hum Vaccin
Immunother. 2021;17(4):943–949. doi: 10.1080/21645515.2020.
1839292

26. Shilling H, Garland SM, Atchison S, et al. Human papillomavirus pre­
valence and risk factors among Australian women 9–12 years after
vaccine program introduction. Vaccine. 2021;39(34):4856–4863. doi:
10.1016/j.vaccine.2021.07.005
27. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy
of BCG vaccine in American Indians and Alaska Natives: a 60-year
follow-up study. JAMA. 2004 5;291(17):2086–91. doi: 10.1001/jama.
291.17.2086
28. Nguipdop-Djomo P, Heldal E, Rodrigues LC, et al. Duration of BCG
protection against tuberculosis and change in effectiveness with
time since vaccination in Norway: a retrospective population-based
cohort study. Lancet Infect Dis. 2016;16(2):219–26. doi: 10.1016/
S1473-3099(15)00400-4
29. Mangtani P, Nguipdop-Djomo P, Keogh RH, et al. The duration of
protection of school-aged BCG vaccination in England: a
population-based case-control study. Int J Epidemiol. 2018;47
(1):193–201. doi: 10.1093/ije/dyx141
30. Abubakar I, Pimpin L, Ariti C, et al. Systematic review and meta-
analysis of the current evidence on the duration of protection by
bacillus Calmette-Guérin vaccination against tuberculosis. Health
Technol Assess. 2013;17(37):1–372, v–vi. 10.3310/hta17370
31. World Health Organization. Diphtheria vaccine: WHO position
paper. Weekly Epidemiol Rec. 2006;91:21–32.
32. Bruce MG, Bruden D, Hurlburt D, et al. Antibody levels and protec­
tion after hepatitis B vaccine: results of a 30-year follow-up study
and response to a booster dose. J Infect Dis. 2016;214(1):16–22. doi:
10.1093/infdis/jiv748
33. World Health Organization. WHO Immunologic Basis For
Immunization: Module 3: Tetanus. 2018 [accessed 2024 Mar 1].
Available from: https://www.who.int/publications/i/item/
9789241513616
34. World Health Organization. Tetanus vaccines: WHO position paper.
Weekly Epidemiol Rec. 2017;92:53–76.
35. Ferlito C, Biselli R, Mariotti S, et al. R. Tetanus-diphtheria vaccination
in adults: the long-term persistence of antibodies is not dependent
on polyclonal B-cell activation and the defective response to
diphtheria toxoid re-vaccination is associated to HLADRB1*01.
Vaccine. 2018;36(45):6718–6725. doi: 10.1016/j.vaccine.2018.09.041
36. World Health Organization. Varicella and herpes zoster vaccines:
WHO position paper, June 2014. Wkly Epidemiol Rec. 2014;89
(25):265–287.
37. Bayer O, Heininger U, Heiligensetzer C, et al. Metaanalysis of vac­
cine effectiveness in varicella outbreaks. Vaccine. 2007;25(37–
38):6655–60. doi: 10.1016/j.vaccine.2007.07.010
38. World Health Organization. Position paper. Mumps virus vaccines.
Wkly Epidemiol Rec. 2007;7:51–60
39. Vashishtha VM, Yadav S, Dabas A, et al. IAP position paper on
burden of mumps in India and vaccination strategies. Indian
Pediatr. 2015;52(6):505–14. doi: 10.1007/s13312-015-0666-2
40. Demicheli V, Rivetti A, Debalini MG, et al. Vaccines for measles,
mumps and rubella in children. Cochrane Database Syst Rev.
2012;2:CD004407. doi: 10.1002/14651858.CD004407.pub3
41. Cohen C, White JM, Savage EJ, et al. Vaccine effectiveness esti­
mates, 2004-2005 mumps outbreak, England. Emerg Infect Dis.
2007;13(1):12–17. doi: 10.3201/eid1301.060649
42. LeBaron CW, Forghani B, Beck C, et al. Persistence of mumps
antibodies after 2 doses of measles-mumps-rubella vaccine.
J Infect Dis. 2009;199(4):552–560. doi: 10.1086/596207
43. Davidkin I, Jokinen S, Broman M, et al. Persistence of measles,
mumps, and rubella antibodies in an MMR-vaccinated cohort: a
20-year follow-up. J Infect Dis. 2008 1;197(7):950–6. doi: 10.1086/
528993
44. World Health Organization. Pneumococcal conjugate vaccines in
infants and children under 5 years of age: WHO position paper –
February 2019. Wkly Epidemiol Rec. 2019;94:85–104.
45. Le Polain De Waroux O, Flasche S, Prieto-Merino D, et al. The
efficacy and duration of protection of pneumococcal conjugate
vaccines against nasopharyngeal carriage: a meta-regression
model. Pediatric Infectious Disease Journal. 2015;34(8):858–864.
doi: 10.1097/INF.0000000000000717
EXPERT REVIEW OF VACCINES 405
46. Madhi SA, Klugman KP, Kuwanda L, et al. Quantitative and quali­
tative anamnestic immune responses to pneumococcal conjugate
vaccine in HIV-infected and HIV-uninfected children 5 years after
vaccination. J Infect Dis. 2009;199(8):1168–76. doi: 10.1086/597388
47. World Health Organization. Rabies vaccines: WHO position paper –
April 2018. Wkly Epidemiol Rec. 2018; 93:201–220. doi: 10.1016/j.
vaccine.2018.06.061
48. Briggs DJ, Schwenke JR. Longevity of rabies antibody titre in reci­
pients of human diploid cell rabies vaccine. Vaccine. 1992;10
(2):125–9. doi: 10.1016/0264-410X(92)90029-J
49. Thraenhart O, Kreuzfelder E, Hillebrandt M, et al. Long-term
humoral and cellular immunity after vaccination with cell culture
rabies vaccines in man. Clin Immunol Immunopathol. 1994;71
(3):287–92. doi: 10.1006/clin.1994.1088
50. Mansfield KL, Andrews N, Goharriz H, et al. Rabies pre-exposure
prophylaxis elicits long-lasting immunity in humans. Vaccine.
2016;34(48):5959–5967. doi: 10.1016/j.vaccine.2016.09.058
51. Chlibek R, Pauksens K, Rombo L, et al. Long-term immunogenicity
and safety of an investigational herpes zoster subunit vaccine in
older adults. Vaccine. 2016 3;34(6):863–8. doi: 10.1016/j.vaccine.
2015.09.073
52. Boutry C, Hastie A, Diez-Domingo J, et al. The adjuvanted recom­
binant zoster vaccine confers long-term protection against herpes
zoster: interim results of an extension study of the pivotal phase 3
clinical trials ZOE-50 and ZOE-70. Clin Infect Dis. 2022;74
(8):1459–1467. doi: 10.1093/cid/ciab629
53. Wendelboe AM, Van Rie A, Salmaso S, et al. Duration of immunity
against pertussis after natural infection or vaccination. Pediatr
Infect Dis J. 2005;24(5 Suppl):S58–61. doi: 10.1097/01.inf.
0000160914.59160.41
54. Vashishtha VM, Bansal CP, Gupta SG. Pertussis vaccines: position
paper of Indian Academy of Pediatrics (IAP). Indian Pediatr. 2013;50
(11):1001–9. doi: 10.1007/s13312-013-0274-y
55. Jenkinson D Duration of effectiveness of pertussis vaccine: evi­
dence from a 10-year community study. Br Med J (Clin Res Ed).
1988;296(6622):612–614. 10.1136/bmj.296.6622.612
56. Campbell H, Amirthalingam G, Andrews N, et al. Accelerating con­
trol of pertussis in England and Wales. Emerg Infect Dis. 2012;18
(1):38–47. doi: 10.3201/eid1801.110784
57. Mueller J, Koutangni T, Guiso N, et al. Comparative efficacy/effec­
tiveness of schedules in infant immunisation against pertussis,
diphtheria and tetanus: systematic review and meta-analysis.
Part 2: whole-cell pertussis vaccine. 2014 [accessed 2024 Jan 6].
Available from: http://www.who.int/immunization/sage/meetings/
2015/april/6_Report_wP_140813.pdf?ua=1
58. World Health Organization. WHO position paper-pneumococcal
vaccines. Duration of Protection and Revaccination. [accessed
2023 Dec 10]. Available from: https://cdn.who.int/media/docs/
default-source/immunization/position_paper_documents/pneumo
coccus/ppv23_additional_summary_duration_protection_revacci
nation.pdf?sfvrsn=ddf846b_3.
59. Butler JC. Pneumococcal polysaccharide vaccine efficacy. An eva­
luation of current recommendations. JAMA. 1993;270
(15):1826–1831. doi: 10.1001/jama.1993.03510150060030
60. Sara E, Oliver SE, Moro P, et al. Epidemiology and prevention of
vaccine-preventable diseases. Haemophilus influenzae [accessed
2024 Jan 5]. Available from: https://www.cdc.gov/vaccines/pubs/
pinkbook/hib.html#:~:text=Hib%20conjugate%20vaccines%20are%
20highly,children%20who%20are%20fully%20vaccinated
61. World Health Organization. Haemophilus influenzae type b (hib)
vaccination position paper – July 2013. Wkly Epidemiol Rec.
2013;88(39):413–426.
62. von Gottberg A, Cohen C, Whitelaw A, et al.; Group for Enteric,
Respiratory, Meningeal Disease Surveillance in South Africa
(GERMS-SA). Invasive disease due to Haemophilus influenzae ser­
otype b ten years after routine vaccination, South Africa,
2003-2009. Vaccine. 2012;30(3):565–571. doi: 10.1016/j.vaccine.
2011.11.066.
63. Ladhani S, Heath PT, Ramsay ME, et al. Long-term immunological
follow-up of children with Haemophilus influenzae serotype
406 V. M. VASHISHTHA AND P. KUMAR
b vaccine failure in the United Kingdom. Clin Infect Dis. 2009;49
(3):372–80. doi: 10.1086/600292
64. Sharma H, Yadav S, Lalwani S, et al. Antibody persistence of two
pentavalent DTwP-HB-Hib vaccines to the age of 15-18 months,
and response to the booster dose of quadrivalent DTwP-Hib
vaccine. Vaccine. 2013;31(3):444–447. doi: 10.1016/j.vaccine.2012.
11.038
65. Gunardi H, Rusmil K, Fadlyana E, et al. DTwP-HB-Hib: antibody
persistence after a primary series, immune response and safety
after a booster dose in children 18-24 months old. BMC Pediatr.
2018;18(1):177. doi: 10.1186/s12887-018-1143-6
66. Hu Z, Rou YL, Chen C, et al. An epidemiological and serological
study on duration of protection after meningococcal group
a polysaccharide (APS) vaccination. In: Poolman JT, editor.
Gonococci and Meningococci. Dordrech: Springer; 1988. p. 199–
207.
67. Reingold AL, Broome CV, Hightower AW, et al. Age-specific differ­
ences in duration of clinical protection after vaccination with
meningococcal polysaccharide A vaccine. Lancet.
1985;2 (8447):114–118. doi: 10.1016/S0140-6736(85)90224-7
68. Andrews N, Borrow R, Miller E Validation of serological correlate of
protection for meningococcal C conjugate vaccine by using effi­
cacy estimates from post-licensure surveillance in England. Clin
Diagn Lab Immunol. 2003;10(5):780–786. doi: 10.1128/CDLI.10.5.
780-786.2003
69. Borrow R, Andrews N, Goldblatt D, et al. Serological basis for use of
meningococcal serogroup C conjugate vaccines in the United
Kingdom: reevaluation of correlates of protection. Infect Immun.
2001;69(3):1568–73. doi: 10.1128/IAI.69.3.1568-1573.2001
70. Nolan T, Booy R, Marshall HS, et al. Immunogenicity and safety of
a quadrivalent meningococcal ACWY-tetanus toxoid conjugate
vaccine 6 years after MenC priming as toddlers. Pediatr Infect Dis
J. 2019;38(6):643–650. doi: 10.1097/INF.0000000000002334
71. Cohn AC, MacNeil JR, Harrison LH, et al. Active bacterial core
surveillance (ABCs) team and MeningNet surveillance partners.
Effectiveness and duration of protection of one dose of
a meningococcal conjugate vaccine. Pediatrics. 2017;139(2):
e20162193. doi: 10.1542/peds.2016-2193
72. Schwartz KL, Kwong JC, Deeks SL, et al. Effectiveness of pertussis
vaccination and duration of immunity. CMAJ. 2016;188(16):E399–
E406. doi: 10.1503/cmaj.160193
73. Mills KH Immunity to Bordetella pertussis. Microbes Infect. 2001;3
(8):655–677. doi: 10.1016/S1286-4579(01)01421-6
74. Klein NP, Bartlett J, Rowhani-Rahbar A, et al. Waning protection
after fifth dose of acellular pertussis vaccine in children. N Engl
J Med. 2012;367(11):1012–1019. doi: 10.1056/NEJMoa1200850
75. Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of
immunity following acellular pertussis vaccination in preadoles­
cents in a North American outbreak. Clin Infect Dis. 2012;54
(12):1730–5. doi: 10.1093/cid/cis287
76. Bell CA, Russell ML, Drews SJ, et al. Acellular pertussis vaccine
effectiveness and waning immunity in Alberta, Canada:
2010-2015, a Canadian Immunization Research Network (CIRN)
study. Vaccine. 2019;37(30):4140–4146. doi: 10.1016/j.vaccine.
2019.05.067
77. Klein NP, Bartlett J, Fireman B, et al. Waning Tdap Effectiveness in
Adolescents. Pediatrics. 2016;137(3):e20153326. doi: 10.1542/peds.
2015-3326
78. Koepke R, Eickhoff JC, Ayele RA, et al. Estimating the effectiveness
of tetanus-diphtheria-acellular pertussis vaccine (Tdap) for prevent­
ing pertussis: evidence of rapidly waning immunity and difference
in effectiveness by Tdap brand. J Infect Dis. 2014;210(6):942–53.
doi: 10.1093/infdis/jiu322
79. Acosta AM, DeBolt C, Tasslimi A, et al. Tdap vaccine effectiveness in
adolescents during the 2012 Washington State pertussis epidemic.
Pediatrics. 2015;135(6):981–9. doi: 10.1542/peds.2014-3358
80. Briere EC, Pondo T, Schmidt M, et al. Assessment of Tdap vaccina­
tion effectiveness in adolescents in integrated health-care systems.
J Adolesc Health. 2018;62(6):661–666. doi: 10.1016/j.jadohealth.
2017.12.011
81. Sridhar S, Luedtke A, Langevin E, et al. Effect of Dengue Serostatus
on Dengue vaccine safety and efficacy. N Engl J Med. 2018;379
(4):327–340. doi: 10.1056/NEJMoa1800820
82. Rivera L, Biswal S, Sáez-Llorens X, et al. Three-year efficacy and
safety of Takeda’s dengue vaccine Candidate (TAK-003). Clin Infect
Dis. 2022;75(1):107–117. doi: 10.1093/cid/ciab864
83. Tricou V Efficacy and safety of Takeda’s tetravalent dengue vaccine
Candidate (TAK-003) after 4.5 years of follow-up. Presented at 8th
Northern European Conference of Travel Medicine; Jun 2022
[accessed 2023 Dec 12]. Available from: https://assets-dam.takeda.
com/raw/upload/v1668754472/legacy-dotcom/siteassets/system/
what-we-do/areas-of-focus/vaccines/info/tides-fact-sheet.pdf
84. World Health Organization. Cholera vaccines: WHO position paper–
August 2017. Wkly Epidemiol Rec. 2017;92(34):477–498.
85. Bhattacharya SK, Sur D, Ali M, et al. 5-year efficacy of a bivalent killed
whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised,
double-blind, placebo-controlled trial. Lancet Infect Dis. 2013;13
(12):1050–1056. doi: 10.1016/S1473-3099(13)70273-1
86. Tandan JB, Ohrr H, Sohn YM, et al. Single dose of SA 14-14-2 vaccine
provides long-term protection against Japanese encephalitis: a
case-control study in Nepalese children 5 years after immunization.
Vaccine. 2007; 25(27):5041–5045. doi: 10.1016/j.vaccine.2007.04.052
87. Khan SA, Choudhury P, Kakati S, et al. Effectiveness of a single dose
of Japanese encephalitis vaccine among adults, Assam, India,
2012-2018. Vaccine. 2021;39(35):4973–4978. doi: 10.1016/j.vaccine.
2021.07.041
88. Preethi L, Alina MS, Chandran L, et al. Duration of seroprotection of
the live attenuated SA-14-14-2 Japanese encephalitis vaccine in
children in India. J Travel Med. 2023;30(2):taac147. doi: 10.1093/
jtm/taac147
89. Kadlecek V, Borja-Tabora CF, Eder-Lingelbach S, et al. Antibody
persistence up to 3 years after primary immunization with inacti­
vated Japanese encephalitis vaccine IXIARO in Philippine children
and effect of a booster dose. Pediatr Infect Dis J. 2018;37(9):e233–
e240. doi: 10.1097/INF.0000000000002124
90. Taucher C, Kollaritsch H, Dubischar KL. Persistence of the immune
response after vaccination with the Japanese encephalitis vaccine,
®
IXIARO in healthy adults: a five year follow-up study. Vaccine.
2019;37(19):2529–2531. doi: 10.1016/j.vaccine.2019.03.030
91. Paulke-Korinek M, Kollaritsch H, Kundi M, et al. Persistence of
antibodies six years after booster vaccination with inactivated
vaccine against Japanese encephalitis. Vaccine. 2015;33
(30):3600–4. doi: 10.1016/j.vaccine.2015.05.037
92. World Health Organization. Typhoid vaccines: WHO position
paper – March 2018. Wkly Epidemiol Rec. 2018;93:153–172.
93. Klugman KP, Koornhof HJ, Robbins JB, et al. Immunogenicity, efficacy
and serological correlate of protection of salmonella typhi vi capsular
polysaccharide vaccine three years after immunization. Vaccine.
1996;14(5):435–8. doi: 10.1016/0264-410X(95)00186-5
94. Lin FY, Ho VA, Khiem HB, et al. The efficacy of a Salmonella typhi Vi
conjugate vaccine in two-to-five-year-old children. N Engl J Med.
2001;344(17):1263–1269.10.1056/NEJM200104263441701
95. Voysey M, Pollard AJ Seroefficacy of Vi polysaccharide-tetanus
toxoid typhoid conjugate vaccine (Typbar TCV). Clin Infect Dis.
2018;67(1):18–24. doi: 10.1093/cid/cix1145
96. Vadrevu KM, Raju D, Rani S, et al. Persisting antibody responses to
®
Vi polysaccharide-tetanus toxoid conjugate (Typbar TCV ) vaccine
up to 7 years following primary vaccination of children < 2 years of
age with, or without, a booster vaccination. Vaccine. 2021 Oct
29;39(45):6682–6690. doi: 10.1016/j.vaccine.2021.07.073
97. Klein NP, Bartlett J, Fireman B, et al. Effectiveness of the live zoster
vaccine during the 10 years following vaccination: real world
cohort study using electronic health records. BMJ. 2023;383:
e076321. doi: 10.1136/bmj-2023-076321
98. World Health Organization. Rotavirus vaccines: WHO position
paper - July 2021. Weekly Epidemiological Rec, 2021;96:301–319.
99. Clark A, van Zandvoort K, Flasche S, et al. Efficacy of live oral
rotavirus vaccines by duration of follow-up: a meta-regression of
randomised controlled trials. Lancet Infect Dis. 2019;19(7):717–727.
doi: 10.1016/S1473-3099(19)30126-4

100. Vesikari T, Karvonen A, Ferrante SA, et al. Efficacy of the pentava­
®
lent rotavirus vaccine, RotaTeq , in Finnish infants up to 3 years of
age: the Finnish extension study. Eur J Pediatr. 2010;169
(11):1379–86. doi: 10.1007/s00431-010-1242-3
101. Phua KB, Lim FS, Lau YL, et al. Rotavirus vaccine RIX4414 efficacy
sustained during the third year of life: a randomized clinical trial in
an Asian population. Vaccine. 2012;30(30):4552–7. doi: 10.1016/j.
vaccine.2012.03.030
102. Vashishtha VM, Kalra A, Choudhury P. Influenza vaccination in
India: position paper of Indian Academy of Pediatrics, 2013.
Indian Pediatr. 2013;50(9):867–74. doi: 10.1007/s13312-013-
0230-x
103. Saha S, Chadha M, Shu Y, et al. Divergent seasonal patterns of
influenza types a and B across latitude gradient in tropical asia.
Influenza Other Respir Viruses. 2016;10(3):176–184. doi: 10.1111/irv.
12372
104. Young B, Sadarangani S, Jiang L, et al. Duration of Influenza vaccine
effectiveness: a systematic review, meta-analysis, and
meta-regression of test-negative design case-control studies.
J Infect Dis. 2018;217(5):731–741. doi: 10.1093/infdis/jix632
105. Ferdinands JM, Fry AM, Reynolds S, et al. Intraseason waning of
influenza vaccine protection: evidence from the US influenza vac­
cine effectiveness network, 2011-12 through 2014-15. Clin Infect
Dis. 2016;64(5):544–550. doi: 10.1093/cid/ciw816
106. Regan AK, Fielding JE, Chilver MB, et al. Intra-season decline in
influenza vaccine effectiveness during the 2016 southern hemi­
sphere influenza season: a test-negative design study and phylo­
genetic assessment. Vaccine. 2019;37(19):2634–2641. doi: 10.1016/j.
vaccine.2019.02.027
107. Rambhia KJ, Rambhia MT. Early bird gets the flu: what should be
done about waning intraseasonal immunity against seasonal
influenza? Clin Infect Dis. 2019;68(7):1235–1240. doi: 10.1093/cid/
ciy748
108. Feikin DR, Higdon MM, Abu-Raddad LJ, et al. Duration of effec­
tiveness of vaccines against SARS-CoV-2 infection and COVID-19
disease: results of a systematic review and meta-regression.
Lancet. 2022;399(10328):924–944. doi: 10.1016/S0140-6736(22)
00152-0
109. Menegale F, Manica M, Zardini A, et al. Evaluation of waning of
SARS-CoV-2 vaccine-induced immunity: a systematic review and
meta-analysis. JAMA Netw Open. 2023;6(5):e2310650. doi: 10.
1001/jamanetworkopen.2023.10650
110. Xu S, Li J, Wang H, et al. Real-world effectiveness and factors
associated with effectiveness of inactivated SARS-CoV-2 vaccines:
a systematic review and meta-regression analysis. BMC Med.
2023;21(1):160. doi: 10.1186/s12916-023-02861-3
111. Pulendran B, Ahmed R. Immunological mechanisms of vaccination.
Nat Immunol. 2011;12(6):509–17. doi: 10.1038/ni.2039
112. Kamat D, Mathur A. Vaccine immunology. In: Vashishtha V Kalra A
(editors) IAP Textbook of Vaccines. 2nd ed. New Delhi: Jaypee
Brothers Medical Publishers; 2020. p. 31–44.
113. Elsner RA, Shlomchik MJ. Germinal Center and Extrafollicular B Cell
Responses in Vaccination, Immunity, and Autoimmunity. Immunity.
2020;53(6):1136–1150. doi: 10.1016/j.immuni.2020.11.006
114. Chen Z, Gao X, Yu D. Longevity of vaccine protection: immunolo­
gical mechanism, assessment methods, and improving strategy.
View. 2022;3(1):20200103.
• This review describes the cellular basis of vaccine-induced
durable humoral immune response. It also provides the evi­
dence and knowledge for the duration of protection by current
vaccines.
115. Stebegg M, Kumar SD, Silva-Cayetano A, et al. Regulation of the
germinal center response. Front Immunol. 2018;9:2469. doi: 10.
3389/fimmu.2018.02469
116. Elgueta R, de Vries VC, Noelle RJ The immortality of humoral
immunity. Immunol Rev. 2010;236(1):139–150. doi: 10.1111/j.1600-
065X.2010.00924.x
117. Siegrist C-A. Vaccine immunology. In: Plotkin S, Orenstein W,
Offit P, editors. Vaccins. 6th ed. Philadelphia, PA: Elsevier-
Saunders; 2013; p. 14–32.
EXPERT REVIEW OF VACCINES 407
• This chapter describes the immune response to different vac­
cines and factors affecting durability of immune response.
118. Chaplin DD. Overview of the immune response. J Allergy Clin
Immunol. 2010;125(2 Suppl 2):S3–23. doi: 10.1016/j.jaci.2009.12.980
119. Wu X, Wu P, Shen Y, et al. CD8+ resident memory T cells and viral
infection. Front Immunol. 2018;9:2093. doi: 10.3389/fimmu.2018.
02093
120. Amanna IJ, Slifka MK, Crotty S Immunity and immunological mem­
ory following smallpox vaccination. Immunol Rev.
2006;211 1:320–337. doi: 10.1111/j.0105-2896.2006.00392.x
121. Amanna IJ, Slifka MK. Mechanisms that determine plasma cell life­
span and the duration of humoral immunity. Immunol Rev.
2010;236(1):125–138. doi: 10.1111/j.1600-065X.2010.00912.x
122. Kato Y, Abbott RK, Freeman BL, et al. Multifaceted effects of antigen
Valency on B cell response composition and differentiation in vivo.
Immunity. 2020;53(3):548–563.e8. doi: 10.1016/j.immuni.2020.08.001
123. Heinz FX, Stiasny K. Distinguishing features of current COVID-19
vaccines: knowns and unknowns of antigen presentation and
modes of action. NPJ Vaccin. 2021;6(1):104. doi: 10.1038/s41541-
021-00369-6
124. Palin AC, Alter G, Crotty S, et al. The persistence of memory:
defining, engineering, and measuring vaccine durability. Nat
Immunol. 2022;23(12):1665–1668. doi: 10.1038/s41590-022-
01359-z.
• Going beyond the simplistic approach of measuring the neu­
tralizing antibody titers, the complete landscape of immune
response is described. The current knowledge, knowledge
gaps, and opportunities for research on vaccine durability
are detailed in this article.
125. Kumar P. “Mix and match” of COVID vaccines (heterologous boos­
ters) In: Vashishtha V, Kumar P, and Wadhwa A, editors. COVID-19
vaccines a comprehensive review. 1st ed. Mumbai: Tree Life Media
Publishers, 2022: p. 269–279.
126. Slifka MK, Amanna I. How advances in immunology provide insight
into improving vaccine efficacy. Vaccine. 2014;32(25):2948–57. doi:
10.1016/j.vaccine.2014.03.078
127. Gordon DM, McGovern TW, Krzych U, et al. Safety, immunogenicity,
and efficacy of a recombinant produced Plasmodium falciparum
circumsporozoite protein-hepatitis B surface antigen subunit
vaccine. J Infect Dis. 1995;171(6):1576–1585. doi: 10.1093/infdis/
171.6.1576
128. Bejon P, White MT, Olotu A, et al. Efficacy of RTS, S malaria vaccines:
individual-participant pooled analysis of phase 2 data. Lancet Infect
Dis. 2013;13(4):319–327. doi: 10.1016/S1473-3099(13)70005-7
129. Graham BS, Gilman MSA, McLellan JS. Structure-Based Vaccine
Antigen Design. Annu Rev Med. 2019 Jan 27;70(1):91–104. doi:
10.1146/annurev-med-121217-094234
130. Bugya Z, Prechl J, Szénási T, et al. Multiple levels of immunological
memory and their association with vaccination. Vaccines (Basel).
2021 Feb 19;9(2):174. doi: 10.3390/vaccines9020174
131. Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants.
Front Immunol. 2013;4:114. doi: 10.3389/fimmu.2013.00114
132. Billeskov R, Beikzadeh B, Berzofsky JA. The effect of antigen dose
on T cell-targeting vaccine outcome. Hum Vaccin Immunother.
2019;15(2):407–411. doi: 10.1080/21645515.2018.1527496
133. Styles TM, Gangadhara S, Reddy PBJ, et al. V2 hotspot optimized
MVA vaccine expressing stabilized HIV-1 Clade C envelope Gp140
delays acquisition of heterologous Clade C Tier 2 challenges in
Mamu-A*01 negative Rhesus Macaques. Front Immunol.
2022;13:914969. doi: 10.3389/fimmu.2022.914969
134. Jegaskanda S, Mason RD, Andrews SF, et al. Intranasal Live
Influenza Vaccine Priming Elicits Localized B Cell Responses in
Mediastinal Lymph Nodes. J Virol. 2018;92(9):e01970–17. doi: 10.
1128/JVI.01970-17
135. Mok DZL, Chan KR. The effects of pre-existing antibodies on
live-attenuated viral vaccines. Viruses. 2020;12(5):520. doi: 10.3390/
v12050520
136. Ciarambino T, Para O, Giordano M. Immune system and COVID-19 by
sex differences and age. Womens Health. 2021;17:17455065211022262.
doi: 10.1177/17455065211022262
408 V. M. VASHISHTHA AND P. KUMAR
137. Cheung F, Apps R, Dropulic L, et al. Sex and prior exposure jointly
shape innate immune responses to a live herpesvirus vaccine. Elife.
2023;12:e80652. doi: 10.7554/eLife.80652
138. Cruz-Tapias P, Castiblanco J, Anaya JM, et al. Major histocompatibility
complex: antigen processing and presentation. In: Anaya J, Shoenfeld Y
Rojas-Villarraga A, editors. Autoimmunity: from bench to bedside [inter­
net]. Bogota (Colombia): El Rosario University Press; 2013. Chapter 10.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK459467/
139. van der Klaauw AA, Horner EC, Pereyra-Gerber P, et al.
Accelerated waning of the humoral response to COVID-19 vac­
cines in obesity. Nat Med. 2023;29(5):1146–1154. doi: 10.1038/
s41591-023-02343-2
140. Jordan A, Carding SR, Hall LJ. The early-life gut microbiome and
vaccine efficacy. Lancet Microbe. 2022;3(10):e787–e794. doi: 10.
1016/S2666-5247(22)00185-9
141. Moroishi Y, Gui J, Nadeau KC, et al. A prospective study of the
infant gut microbiome in relation to vaccine response. Pediatr Res.
2023;93(3):725–731. doi: 10.1038/s41390-022-02154-0
142. Xu X, Wu Y, Kummer AG, et al. Assessing changes in incubation
period, serial interval, and generation time of SARS-CoV-2 variants
of concern: a systematic review and meta-analysis. BMC Med.
2023;21(1):374. doi: 10.1186/s12916-023-03070-8
143. Varghese T, Kang G, Steele AD. Understanding rotavirus vaccine
efficacy and effectiveness in countries with high child mortality.
Vaccines (Basel). 2022;10(3):346. doi: 10.3390/vaccines10030346
144. Parker EP, Ramani S, Lopman BA, et al. Causes of impaired oral
vaccine efficacy in developing countries. Future Microbiol. 2018;13
(1):97–118. doi: 10.2217/fmb-2017-0128
145. Reuman PD, Bernstein DI, Keely SP, et al. Influenza-specific ELISA
IgA and IgG predict severity of influenza disease in subjects pre­
screened with hemagglutination inhibition. Antiviral Res. 1990;13
(3):103–10. doi: 10.1016/0166-3542(90)90026-4
146. Lavelle EC, Ward RW. Mucosal vaccines — fortifying the frontiers. Nat
Rev Immunol. 2022;22(4):236–250. doi: 10.1038/s41577-021-00583-2
147. Nuwarda RF, Alharbi AA, Kayser V. An overview of influenza viruses
and vaccines. Vaccines (Basel). 2021;9(9):1032. doi: 10.3390/
vaccines9091032
148. Carabelli AM, Peacock TP, Thorne LG, et al. SARS-CoV-2 variant
biology: immune escape, transmission and fitness. Nat Rev
Microbiol. 2023;21:162–177. doi: 10.1038/s41579-022-00841-7
149. Patriarca PA, Wright PF, John TJ. Factors affecting the immunogeni­
city of oral poliovirus vaccine in developing countries: review. Rev
Infect Dis. 1991;13(5):926–39. doi: 10.1093/clinids/13.5.926
150. Otasowie CO, Tanner R, Ray DW, et al. Chronovaccination: Harnessing
circadian rhythms to optimize immunisation strategies. Front Immunol.
2022;13:977525. doi: 10.3389/fimmu.2022.977525
151. Cervantes-Silva MP, Carroll RG, Wilk MM, et al. The circadian clock
influences T cell responses to vaccination by regulating dendritic
cell antigen processing. Nat Commun. 2022;13(1):7217. doi: 10.
1038/s41467-022-34897-z
152. Cohen J. How long do vaccines last? The surprising answers may help
protect people longer. Science Magazine [accessed 2023 Dec 23].
Available from: https://www.science.org/content/article/how-long-
do-vaccines-last-surprising-answers-may-help-protect-people-longer
153. Beukema M, Gong S, Al-Jaawni K, et al. Prolonging the delivery of
influenza virus vaccine improves the quantity and quality of the
induced immune responses in mice. Front Immunol.
2023;14:1249902. doi: 10.3389/fimmu.2023.1249902
154. Lee JH, Sutton HJ, Cottrell CA, et al. Long-primed germinal centres
with enduring affinity maturation and clonal migration. Nature.
2022;609(7929):998–1004. doi: 10.1038/s41586-022-05216-9
155. Plotkin SA. Vaccines: correlates of vaccine-induced immunity. Clin
Infect Dis. 2008 1;47(3):401–409. doi: 10.1086/589862.
• This review describes the correlates of vaccine-induced immu­
nity: whether the correlates are absolute, relative of surrogate
in different situations. The role of cell-mediate immunity as
correlate of protection against disease is also described.
156. Farber DL, Yudanin NA, Restifo NP. Human memory T cells: gen­
eration, compartmentalization and homeostasis. Nat Rev Immunol.
2014;14(1):24–35. doi: 10.1038/nri3567
157. Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral
immunity after smallpox vaccination. Nature Med. 2003;9
(9):1131–1137. doi: 10.1038/nm917
158. Crotty S, Felgner P, Davies H, et al. Cutting edge: long-term B cell
memory in humans after smallpox vaccination. J Immunol.
2003;171(10):4969–4973. doi: 10.4049/jimmunol.171.10.4969
159. Duan LJ, Cui XM, Zhu KL, et al. SARS-CoV-2 vaccine-induced anti­
body and T cell response in SARS-CoV-1 survivors. Cell Rep. 2022;40
(9):111284. doi: 10.1016/j.celrep.2022.111284
160. McKee AS, Munks MW, MacLeod MK, et al. Alum induces innate
immune responses through macrophage and mast cell sensors,
but these sensors are not required for alum to act as an adjuvant
for specific immunity. J Immunol. 2009;183(7):4403–4414. 10.
4049/jimmunol.0900164
161. Einstein MH, Baron M, Levin MJ, et al. Comparative immunogenicity
and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-
6/11/16/18 vaccine: follow-up from months 12–24 in a phase III
randomized study of healthy women aged 18–45 years. Hum
Vaccin. 2011;7(12):1343–1358. doi: 10.4161/hv.7.12.18281
162. Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles
to new developments. Nat Rev Immunol. 2021;21(2):83–100. doi:
10.1038/s41577-020-00479-7
163. Prabhakaran M, Matassoli F, Leggat D, et al. Adjuvanted SARS-CoV-
2 spike protein vaccination elicits long-lived plasma cells in nonhu­
man primates. Sci Transl Med. 2024;16(728):eadd5960. doi: 10.
1126/scitranslmed.add5960