Best Practive Clinical 2021

Best Practice & Research Clinical Obstetrics and Gynaecology 76 (2021) 66e82
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn
Vaccinations in the newborn

Tejasvi Chaudhari, MBBS, MD, DNB, DCH, FRACP, CCPU, Senior
Staff Neonatologist *
Australian National University Medical School, Canberra, Australia
a b s t r a c t
Keywords:
Neonate Neonatal immunisation includes vaccination in the first 4 weeks of
Vaccine life (Neonatal period) as well as in high-risk preterm infants in the
Immunisation first few months (until 44 weeks corrected gestational age). Neo-
Preterm nates have an immature immune system, which renders them
Adjuvant highly susceptible to life-threatening infections. This highlights the
Immune system
importance of vaccination in this vulnerable population; however,
at the same time also making it challenging because of their
inability to generate a protective immune response. Other chal-
lenges include interference from maternal antibodies and exces-
sive skewing towards T Helper Cell Type 2 (Th2) immunity. Despite
these challenges, several vaccines have been developed and
proven safe and effective at birth. Presently, there are 3 vaccines e
Hepatitis B vaccine, Bacillus Calmette-Guerine (BCG) and Oral Polio
vaccine (OPV) widely used in neonates, which provides evidence
that certain antigen-adjuvant combinations can elicit protective
neonatal responses. This review focusses on current vaccinations
in neonates, including preterm infants and highlights some novel
approaches to enhance neonatal vaccination.
© 2020 Published by Elsevier Ltd.
Introduction
During the Millennium Development Goal era from 2000 to 2015, the under-five mortality rate was
reduced by 53%. Despite the success, in 2018, an estimated 5.3 million children died in the first 5 years,
* Department of Neonatology, Centenary Hospital for Women and Children, Canberra Hospital, Woden, 2606, Australian
Capital Territory, Australia.
E-mail address: tejasvi.chaudhari@act.gov.au.
https://doi.org/10.1016/j.bpobgyn.2020.09.004
1521-6934/© 2020 Published by Elsevier Ltd.
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T. Chaudhari Best Practice & Research Clinical Obstetrics and Gynaecology 76 (2021) 66e82
with almost half of these in the first month of life [1]. The World Health Organization (WHO) has therefore
included in their 2030 Sustainable Development Goal (SDG), to reduce neonatal mortality to 12 per 1000
live births and under-5 mortality to 25 per 1000 live births for all countries [2]. Many of these deaths are
attributed to vaccine preventable illness such as pneumonia and diarrhoea that occur before routine
vaccination, which commences at 6e8 weeks of age under The WHO Expanded Programme on Immu-
nisation (EPI). Certain vaccines such as flu vaccine cannot be used in infants less than 6 months.
Furthermore, first dose under EPI does not provide immediate protection and multiple doses are required,
making infants more susceptible in the first 6 months of life. To achieve SDG targets, several strategies are
proposed. Maternal and neonatal immunisations could potentially address some of these goals [3].
Vaccines administered during pregnancy can protect mothers against infection-related morbidity
and mortality and as a result improve neonatal death, stillbirth, and preterm birth. Maternal influenza,
tetanus and pertussis vaccines provide good examples [4]. In addition, transplacental transfer of
immunoglobulin G (IgG) antibodies generated through maternal vaccination protects newborns and
young infants in the first few months of life. Preterm infants, however, are often born prior to antibody
transfer, making them more susceptible to infections. Additionally, maternal antibodies may interfere
with infant vaccine responses and reduce bioavailability of orally administered vaccines [5]. Birth is the
most reliable point of health care contact, and therefore, neonatal vaccines achieve high population
uptake. Furthermore, there is emerging evidence of heterologous benefits of the BCG vaccine, which
may be the best in early life [6]. This highlights the importance of neonatal immunisation in reducing
morbidity and mortality in young infants.
Neonatal immunity and challenges to vaccination
A newborn's immune system is physiologically immature at birth, which increases its susceptibility
to pathogens. This is thought to be necessary to avoid alloimmune reactions between the foetus and
mother and an adaptation to the exposure to large amounts of new antigens in early life, skewing the
response to suppression [7]. Mohr and Siegrist described the neonatal immune system as characterised
by anti-inflammatory, rather than pro-inflammatory [8]. The distinct composition of human newborn
cord blood plasma includes soluble mediators such as maternal antibodies, high levels of immuno-
suppressive adenosine and low levels of complement, which are important to trigger adaptive immune
responses [7]. There is good evidence that human neonates have reduced CD4þ T cell immunity,
particularly Th1 helper T cells. Upon exposure to an immune stimulus, newborns express an innate Th2
response and weak Th1 response. This is due to the decreased number of antigen-presenting cells
(APC) in newborns, which results in decreased pro-inflammatory mediators like Interleukin 12 (IL-12)
needed for Th1 differentiation [9]. The low responsiveness of neonatal T cells to immune stimulus has
an impact on the intrinsic ability of T cells to respond to vaccines and pathogens [10].
Most of the newborn's serum immunoglobulins are derived from the transfer of maternal immu-
noglobulin G (IgG) across the placenta during the third trimester of pregnancy. Neonatal B-cell dif-
ferentiation pathway is skewed towards memory B cells rather than plasma cells that limit their ability
to produce antibodies. Other factors contributing to reduced humoral immunity include limited
antibody repertoire, reduced T1 helper T cells, fewer follicular dendritic cells and germinal centres and
reduced signalling through B cell receptor (BCR) pathway [11]. Thus, a vaccinated neonate will produce
lower antibody titres with less-functional antibody as compared to an older infant.
Maternal antibodies transferred through the placenta or in milk also interfere with effective
vaccination through immunomodulation. The vaccine antigen binds with both the BCR and maternal
antibody-Fc complex on the B cell, which inhibits antibody production [12].
Despite the challenges listed above, several vaccines have been shown to elicit a clinically significant
immunogenic response at birth. Studies of Bacillus Calmette-Guerine (BCG) immunisation have
demonstrated that BCG vaccination can induce strong Th1 type immune response in addition to having
non-specific or heterologous effects against other unrelated infections [6]. Studies of hepatitis B and
oral polio immunisation at birth have also shown that the priming of memory B cells can be achieved in
neonates. A number of strategies such as alternative routes of delivery, novel vaccine configurations,
improved innate receptor agonists and optimised antigen-adjuvant combinations have been used to
improve immunogenicity of vaccines in neonates [11].
67
It is important to note that the functional activity of APC's increase with time, and the increase
occurs in proportion to time since birth rather than ‘gestational’ age, which suggests that it is controlled
by exposure to the environment and removal of maternal influence [13]. This is particularly relevant
when preterm babies are vaccinated.
Vaccines given at birth
BCG vaccine
Vaccination type
The BCG vaccine is a live attenuated Mycobacterium bovis vaccine.
Indication
BCG vaccine is administered in the first few days of life in most low- and middle-income countries
to prevent tuberculous meningitis and miliary tuberculosis (TB). It is not generally used in developed
countries like UK, USA and Australia because of a relatively low prevalence of TB. In these countries,
BCG is recommended for high-risk infants such as travellers to high-risk areas, infants born to migrants
from high-risk countries, high-risk areas where TB is endemic and to health care workers at increased
risk of repeated exposure.
Background
BCG vaccine was developed by Dr Calmette and Dr Guerin at the Pasteur Institute in Lille, France.
The vaccine was first administered to humans in 1921, and remains the only vaccine against TB in
general use. It is the most widely administered vaccine in the world, with over 120 million doses
administered annually each year [14].
The original strains were serially passaged until lyophilisation became available as a method of
preserving mycobacteria by 1961. Since then, several sub-strains have been developed and named after
their manufacturer and the site of origin (e.g. TICE, Connaught, Moscow and Tokyo) [15].
Majority of the world's population is supplied with BCG vaccine procured by UNICEF. To limit strain
variation within vaccine production, WHO has established reference reagents for BCG vaccines. Different
strains tend to be used interchangeably, with no conclusive evidence that one strain is better than other.
Presentation
The ensuing data will focus on Danish 1331 BCG strain produced by AJ Vaccines and used in several
countries like the UK and New Zealand [16].
-The BCG vaccine AJV comes as a powder and solvent for suspension for injection in a multidose
container.
Preparation/dilution
- Reconstitute BCG vaccine using 1 mL of solvent using a 1 or 2 mL syringe fitted with a 25 mm long
needle.
- The rubber stopper must not be wiped with any antiseptic or detergent, if alcohol is used, it must be
allowed to evaporate before penetration by the syringe and needle
- Carefully invert the vial a few times to dissolve the powder completely. DO NOT SHAKE
- The reconstituted vaccine should be used strictly within a 4e6 h period
Dosage/interval
BCG vaccine is a single dose given by intradermal injection:
- In newborns and infants <12 months of age, the dose is 0.05 mL

- In children 12 months of age and adults, the dose is 0.1 mL
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In countries with a high incidence of TB, the vaccine should be given at birth or as soon as possible
after birth.
Route/administration
Use a short (10 mm) 26e27 gauge needle with a short bevel. The risk of spillage can be minimised
by using an insulin syringe that already has a needle attached.
BCG vaccine is administered intradermally in the arm (left arm by convention), over the distal
insertion of the deltoid muscle onto the humerus (approx. One-third down the upper arm).
Monitoring
-Observed for an allergic reaction for up to 15e20 min after receiving immunisation
- The potential risk of apnoea in preterm infants particularly <28 weeks of gestation. Monitor
cardiorespiratory status for 48e72 h post administration
Contraindication
BCG is a live vaccine, hence contraindicated in immunocompromised neonates from the following
group:
- Infants with known or suspected HIV infection (for example born to HIV-positive mothers) until HIV
infection is excluded
- Infants exposed to immunosuppressive treatment in utero or through breastfeeding (e.g. TNF-alpha
antagonists)
- Congenital cellular immunodeficiencies
In older children and infants, BCG is contraindicated if they have had any known hypersensitivities
to BCG vaccine components, malignancies such as leukaemias, lymphomas or are on immunosup-
pressive therapies.
Precautions
- Caution while administering the vaccine too deep as this increases the risk of discharging ulcer,
lymphadenitis and abscess formation
- Infants with active skin disease such as dermatitis, eczema at or near the site of infection
- Sick or febrile infants
- Infants on treatment for latent TB as the treatment can inactivate the BCG vaccine.
Adverse reactions
In general, the BCG vaccine exhibits an excellent safety profile with very few serious adverse effects
despite extensive use.
- Almost all vaccine recipients experience mild local reaction characterised by a papule, which may
be red, tender and indurated. The papule evolves into an ulcer followed by superficial scarring
within 2e5 months [17].
- Axillary and cervical lymphadenopathy, generally mild, however, in some cases may be severe
causing suppuration requiring drainage
- Disseminated BCG infection is a rare complication, occurring in less than one per million in-
dividuals. It has been reported in children with congenital immune disorders such as severe
69
combined immunodeficiency, chronic granulomatous disease and the acquired immunodeficiency

syndrome
- Osteitis and osteomyelitis are rare complications as is anaphylactic or allergic reaction
Storage
-BCG vial should be stored at 2 C-8 C with protection from light. Do not freeze
-Exposure to heat and light both before and after reconstitution may result in a loss of potency.
Stability
-Shelf life is 2 years

-Use immediately after reconstitution
Special comments
-The protective efficacy of the neonatal BCG vaccine is 64%e73% against meningitis and 77%e78%
against miliary TB [7]. The efficacy varies between countries, possibly related to varying environ-
mental exposure, strain variations in BCG preparations [18], genetic or nutritional differences and
other factors, such as sunlight exposure and poor cold chain maintenance [19]. The greatest benefit
of BCG immunisation has been observed in regions where both the risk of TB and the rates of
vaccine coverage are highest.
- BCG vaccine may not protect against primary pulmonary infection or reactivation of latent TB, and
protective efficacy declines to non-significant levels after 10e20 years [11].
- BCG induces a potent Th1 immune response to mycobacterial antigens without the need for
exogenous adjuvant even in neonates making it suitable for vaccination during this period
- Neonatal BCG vaccination may also have non-specific, heterologous beneficial effects that reduce
mortality and morbidity from non-tuberculous infections as well as allergic diseases. BCG can boost
cytokine and cellular response to HBV and oral polio vaccine (OPV) in neonates, possibly by
influencing dendritic cell maturation. A similar effect has been demonstrated on the pneumococcal
conjugate vaccine [20].
- Co-administration of BCG with birth dose of hepatitis B is safe and strongly recommended
Evidence summary
- In one systematic review and meta-analysis including 14 studies and 3855 participants who
received BCG vaccination, BCG had an overall protective efficacy of 19% (risk ratio [RR] 0.81 and 95%
CI 0.71e0.92) [21] as compared to unvaccinated children. In a restricted analysis of studies in which
BCG was administered at birth, the protective efficacy of 28% (RR 0.72 and 95% CI 0.56e0.93) was
observed.
- Mangtani P et al. [18] performed another meta-analysis, which included 18 trials reporting pul-
monary TB and 6 reporting miliary or meningeal TB. They found that the absence of prior Myco-
bacterium tuberculosis infection or sensitisation with environmental mycobacteria provided higher
efficacy of BCG against pulmonary TB (incidence rate ratio [IRR], 0.26 and 95% confidence interval
[CI], 0.18-0.37), and possibly against miliary and meningeal TB (IRR, 0.1; 95% CI, 0.01-0.77). Pro-
tection was higher in trials further from the equator where environmental mycobacteria are less
and with a lower risk of diagnostic detection bias
- A systematic review analysed adverse events following BCG immunisation [22]. There was sub-
stantial variation in the reported rate of lymphadenitis across countries and across periods, which
ranges from as low as 0.41 per 1000 vaccinated children in Saudi Arabia in 2012 to as much as 308
per 1000 in HIV-positive vaccinated children in Haiti in 1994. There was substantial variation in the
reported rate of disseminated BCG across countries and across periods, which ranges from 1.81 per
1000 in South Africa to 167 per 1000 in France.
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- Badurdeen et al. [23] studied immunogenicity and the safety of BCG vaccine in preterm (26e37
weeks) and/or low birth weight (0.69e2.5 kg at birth) neonates in the first 7 days as compared to
later points or in normal birth weight infants through a systematic review and meta-analysis. They
found no difference in the incidence of death, systemic disease, scar formation and immunogenicity
(through tuberculin skin test conversion). Based on their findings, they recommended early BCG
vaccination in stable infants who are preterm and/or have low birth weight to improve uptake.
Hepatitis B vaccine
Vaccination type
Hepatitis B vaccine is an alum-adjuvanted vaccine containing recombinant hepatitis B surface an-
tigen (HBsAg).
Indication
Hepatitis B vaccine is recommended for the primary immunisation of ALL infants against infection
caused by the hepatitis B virus.
Background
Hepatitis B is an infection caused by hepatitis B virus that primarily affects the liver. The virus is
transmitted by inoculation through broken or penetrated skin, or by mucosal contact with blood or
other body fluids (mainly vaginal fluids and semen) from an infectious person. Over 2 billion in-
dividuals have the serological evidence of hepatitis B (HBV) infection worldwide. As antiviral therapy is
not that effective against the virus, primary prevention through immunisation is the most effective way
to control the spread of infection [24].
Presentation
Current vaccines available today use recombinant DNA technology to express HBsAg in yeast cells.
The vaccine is available either as a single preparation (monovalent- Engerix B, HB-Vax-II) or in com-
bined form (multivalent-Infanrix hexa, Hexaxim, Pediarix, Vaxelis and Twinrix). Alum, a chemical
compound, which contains aluminium salts, is added as an adjuvant.
- Each 0.5 mL monodose vial or prefilled syringe of Engerix B contains 10 mg of HBsAg protein and
0.25 mg aluminium hydroxide (for subjects up to 15 years of age, including neonates)
- Infanrix Hexa 10 mg/0.5 mL
- HB-Vax II e 5 mg/0.5 mL
The ensuing discussion will focus on Engerix B paediatric formulation [25].
No dilution required. Shake vigorously before use.
Dosage/interval
-0.5 mL IM
-Should be given to all infants as soon as possible after birth
-The greatest benefit is seen when the first dose is administered within 24 h
-The first dose must be given within 7 days
-A total of four doses should be administered at either:
Birth, 2 months, 4 months and 6 months OR
Birth, 2 months, 4 months and 12 months
-Babies born at < 32 weeks gestation or with a birth weight <2000 g, are recommended to have
their vaccine given at 0, 2, 4 and 6 months of age and either:
71
Measure hepatitis B antibodies at 7 months of age and give a booster at 12 months of age if
antibody titre is < 10 mUnits/mL OR
Give a booster at 12 months without measuring antibody titre.
Route/Administration
-Give into anterolateral thigh, not buttocks at birth. Vaccine may be administered subcutaneously in
patients with thrombocytopenia or bleeding disorders, but the immune response may be lower.
-Can be given at the same time as Vitamin K
-Give at a separate site from other concurrently administered vaccines/IM injections
-Subsequent doses are given in the form of Infanrix Hexa: (Diphtheria; Tetanus; Acellular Pertussis;
Hepatitis B; Haemophilus Influenzae type B (Hib) and Inactivated Poliomyelitis)
Monitoring
-HBsAgs and hepatitis B surface antibodies should be measured in infants born to mothers with
chronic HBV 3e12 months after completing the primary vaccine course
-Potential risk of apnoea in preterm infants particularly <28 weeks of gestation when administering
primary immunisation series. Monitor cardiorespiratory status for 48e72 h post administration
Contraindication
Serious allergic reaction (e.g. anaphylaxis) after previous vaccine dose or to a component of vaccine,
including yeast.
Precautions
-Postpone vaccination in significant acute illness or fever >38.5 C

-IM injections should not be given if there is severe thrombocytopenia or a coagulation disorder like
haemophilia
-Use caution in latex sensitive individuals as tip caps of the pre-filled syringes may contain natural
rubber latex
Adverse reactions
-Soreness at the injection site is common

-Fever greater than 37.7 C occurs in 1%e6%
Storage
-Store between 2 C and 8 C. Do NOT freeze as this reduces potency

-Storage above or below the recommended temperature may decrease potency
Stability
-The shelf life of ENGERIX-B is three years from the date of manufacture when stored between þ2 C
and þ8 C.
-The monodose vial and pre-filled syringe presentations are for use in a single patient only and any
residue must be discarded.
Special comments
- Efficacy of the HBV vaccine is measured by its ability to induce hepatitis B surface antibody (Hbs Ab)
at a titre of >10 IU/L [23].
- In healthy infants, 30%e40% protection against HBV infection is achieved with one dose of the
vaccine, 50%e75% protection with two doses and >90% with three doses [19].
72
- HBV immunisation induces equivalent antibody responses in newborns and adults, which suggest
the capacity of the newborn to develop antibody responses to appropriate immune stimulus [26].
- Booster doses are not currently recommended for fully vaccinated, immunocompetent individuals
- Preterm neonates <2000 g or <32 weeks do not respond as well to hepatitis B vaccine as full term
babies. They should have the usual dosing schedule and then consider a booster dose at 12months [27]
-All newborns born to HBsAg-positive mothers, must receive both a birth dose of hepatitis B vaccine
and hepatitis B immune globulin (HBIG) in separate thighs preferably within 12 h of birth. This
regimen results in the seroconversion rates of 96%. The efficacy of HBIG decreases markedly if given
after 48 h of birth [28].
Evidence summary
- van den Ende et al. [29] performed a systematic review on immunogenicity of Engerix B (GSK HepB,
GSK, Belgium) vaccine in children. They found that primary 3-dose vaccination of healthy infants
and children, including infants born to HBsAg-positive mothers, using the standard 0, 1, 6 month
schedule was associated with seroprotection rates 96.0%. Children with severe underlying disease,
including human immunodeficiency virus infection and cancer had lower seroprotection rates. The
vaccine had a clinically acceptable safety profile in all the populations studied.
- Dolhain et al. [30] performed a systematic review of 6 clinical trials conducted in the South-East
Asia and Western Pacific Regions, investigating vaccination regimens with >3 doses of HBV-
containing vaccines in infants, including a monovalent HBV vaccine birth dose and 1 dose of
Infanrix Hexa (GSK's hexavalent DTPa-HBV-IPV/Hib vaccine). They found in all studies, three pri-
mary doses of hexavalent DTPa-HBV-IPV/Hib vaccine administered during the first 6 months of life,
which induced a robust immune response to all vaccine antigens and had a clinically acceptable
safety profile.
Oral polio vaccine
Vaccination type
OPV is a live attenuated vaccine.
Indication
OPV is used in high risk or polio-endemic countries for the prevention of poliomyelitis in all age
groups. In these countries, an OPV dose (called ‘zero’ dose) is recommended at birth [11] and therefore
remains the first mucosal vaccine received by newborns.
Background
Poliomyelitis (also referred to as ‘polio’), is an acute infectious disease caused by poliovirus. Poliovirus
is a neurotropic enterovirus that can affect motor neurons of the spinal cord and brainstem causing
paralysis or death in a matter of hours. There are 3 serological types (type 1, 2 or 3). The virus is
transmitted by faeco-oral route and mainly affects children less than 5 years. There is no cure for polio,
but 2 highly effective vaccines e OPV and inactivated polio vaccine (IPV) are available for prevention [11].
OPV has been the vaccine of choice for controlling poliomyelitis in many developing countries, and
for the global polio eradication initiative, because of low cost, ease of oral administration, induction of
intestinal immunity and transmission of the attenuated virus from vaccinated children to the non-
immune population. A trivalent OPV formulation containing all 3 serotypes was used worldwide
until April 2016, when it was replaced with bivalent (type 1 and type 3). This was due to eradication of
type 2 polioviruses as well as association between type 2 polioviruses and vaccine-associated paralytic
poliomyelitis (VAPP). IPV-containing vaccine is the only vaccine available for routine infant and
childhood immunisation in most middle- and upper-income countries. It is safe, highly effective and
can be combined with other vaccines given by intramuscular injection [35].
A combination of bivalent OPV (bOPV) vaccine and IPV is recommended by the WHO EPI for routine
infant immunisation. In this context, IPV provides protection against disease caused by type 2 polio-
viruses and a boost in immunity to types 1 and 3 (11).
73
Presentation
The WHO OPV is manufactured in France by Sanofi Pasteur. The vaccine is an oral suspension in a
multidose vial (2 mL vial e 20 doses of 0.1 mL or 2 drops). Each box has 10 vials.
There is no extrinsic adjuvant within the OPV formulation.
The vial must be shaken gently to avoid any foaming, but sufficiently to obtain a homogeneous
mixture of the contents.
Dosage/interval
Most countries who follow the WHO EPI schedule for routine infant immunisation administer bOPV
at birth (zero dose) and at 6, 10 and 14 weeks of age and one dose of IPV at 14 weeks of age.
For countries that only use IPV, the WHO recommends three doses for countries that use a 2, 4 and 6
month schedule for routine infant immunisation and four doses for countries that use a 6, 10 and 14
week schedule; the fourth dose should be administered 6 months after the third dose.
For countries that have introduced sequential IPV-oral poliovirus vaccine (OPV) schedules, one or
two IPV doses followed by a minimum of two OPV doses are recommended [31e33].
Route/administration
-OPV must be administered orally.

-Gently squeeze the child's cheeks to make them open their mouth. The vaccine dose is 2 drops
(0.1 mL) allowed to fall off onto the tongue from the multi-dose dropper
Monitoring
-No immediate monitoring is necessary

- The mother is instructed to withhold hot fluids for half an hour after the drops
Contraindication
- Severe allergy to any component (including streptomycin and neomycin) of the vaccine or a reaction
to previous OPV dose
- Primary immune deficiency or secondary immune deficiency for e.g. immunosuppressive therapy,
leukaemia and malignancies
- Symptomatic HIV infection. OPV can still be given to children with unknown HIV status or who are
asymptomatic in resource limited areas
Precautions
- OPV must not be injected

- Caution using OPV in close contacts of patients with immunodeficiency
- OPV is safe to be given to sick children with diarrhoea or other illnesses
Adverse reactions
- VAPP is a rare, but important complication due to the reversion of the vaccine virus to neuro-
virulence. The reported incidence varies between 1.4 and 2.8 million doses
- VAPP usually occurs after 4e8 weeks. Majority occur after the first dose
- The removal of OPV2 from the vaccine in 2016 has since reduced the incidence significantly
- Other adverse effects include myalgia, arthralgia, fever and tiredness
74
Storage
-Long term storage is recommended at 20 C in a deep freezer
Stability
- Once thawed, the liquid vaccine can be stored for 6 months between 2 C and 8 C
- During an immunisation session, OPV should be kept in ice or on the ice pack
Special comments
- If the global polio eradication programme is successful, all OPV vaccination will be replaced with IPV
within three to four years of interrupting the transmission of all circulating polioviruses [34].
- Any vaccination program in high-risk countries must incorporate at least one dose of IPV to OPV
schedule to protect against serotype 2
- A birth dose of live OPV may induce heterologous (‘non-specific’) beneficial effects similar to BCG
vaccine [35].
Evidence summary
-Mateen et al. [36] performed a systematic review to evaluate the efficacy and adverse events in
infants given OPV (trivalent) or IPV at birth. Among the 5257 infants from 13 countries who received
OPV, they found that the percentage of newborns who seroconverted at 8 weeks ranged between
6% and 42% for poliovirus type 1 and 2, 63% for type 2 and 1 and 35% for type 3. There were four
studies of IPV in newborns with a seroconversion rate of 8%e100% for serotype 1, 15%e100% for
serotype 2 and 15%e94% for serotype 3, measured at 4e6 weeks of life. No serious adverse events
related to OPV or IPV doses at birth were reported in these studies, including no cases of acute
flaccid paralysis.
-Macklin et al. [37] evaluated the effect of vaccine schedules on humoral and intestinal immunity
against poliovirus through a systematic review and network meta-analysis. They found that the
proportion of individuals who developed intestinal mucosal immunity to type 2 poliovirus was
similar following three doses of bOPV with types 1 and 3 (30%) to that of three doses of bOPV with
IPV (25%). Additional IPV doses improved humoral immunity against type 2 serotype but did not
enhance intestinal mucosal immunity. All vaccine schedules showed a seroconversion rate of 80%
for serotype 1 and at least 88% for serotype 3.
Immunisation in preterm infants
Globally, 10.6% of babies are born preterm equating to an estimated 14.84 million births in a year
[38]. Preterm infants have an immature immune system as compared to their term counterparts
making them more susceptible to vaccine preventable infections [13]. Low birth weight infants are at
increased risk of pertussis infection and hospitalisation as compared to normal birth weight infants
[39]. In a recent study from Netherlands, preterm infants were more likely to need hospitalisation (12%
vs 8%), intensive care admissions and spent a longer time in ICU [40]. Invasive pneumococcal diseases
(IPD) are a common cause for neonatal sepsis. Preterm and low birth weight infants are at increased
risk of pneumococcal disease as compared to term infants. Riise et al. reported a 1.8-fold increased risk
of IPD for all serotypes among preterm when compared with full-term children 0e2 years [41]. Preterm
infants are also more vulnerable to severe rotavirus infection. Among children born preterm, those
with a low (<2500 g) or very low birth weight (<1500 g) present the highest risk of rotavirus hospi-
talisations (OR: 2.6 and 95% CI: 1.6e4.1 and OR: 1.6 and 95% CI 1.3e2.1, respectively) [42].
It is logical to assume that the impaired immune systems of preterm infants could significantly
suppress responses to vaccine antigens and reduce the protective effects of vaccination. Fortunately,
75
postnatal maturation, which begins upon exposure to environmental antigens, occurs in preterm in-
fants at a speed comparable to that of full-term infants [13]. Furthermore, there is reduced interference
from maternal antibodies in preterm infants, which may improve vaccine responses. Several studies
have shown that the immune response is high enough to ensure short- and long-term protection in
most premature infants. In most developed countries, immunisation schedule in premature babies
consists of a hexavalent preparation (e.g. Infanrix Hexa) containing combined diphtheria and tetanus
toxoids, acellular pertussis antigens, hepatitis B (recombinant) surface antigen, inactivated polio virus
and adsorbed conjugated Haemophilus; pneumococcal conjugate vaccine (e.g. Prevanar) and rotavirus
vaccine (e.g. Rotarix).
D'Angio et al. [43] demonstrated optimal antibody titres against diphtheria, tetanus and polio in
preterm infants after 3 doses DTwP, Hib and IPV vaccines. Similarly, Omen ~ aca et al. [44] reviewed out-
comes of GSK's hexavalent vaccine Infanrix hexa (DTPa-HBV-IPV/Hib) in 10 clinical studies in preterm
infants up to 24 weeks gestation. They showed that up to 92.5% of these infants were seropositive to all
vaccine antigens after 3-dose primary vaccination (98.7% for diphtheria and tetanus; 100% for polio se-
rotypes 1 and 2, 90.9% for type 3 and 92.4% for pertussis, 92.5% for Hib). Several studies on response to
pertussis and Hib vaccine in preterm infants have shown decreased immunogenicity as compared to term
infants. However, despite the difference, the antibody levels against the different antigens were still
higher than what is considered as a protective level [45]. With regard to hepatitis B vaccine, studies in
preterm babies have shown variable effects, where some trials showing reduced seroconversion in babies
<2000 g [46], while others showing adequate seroconversion by 30 days of age [47] regardless of birth
weight. Omeneca et al. [44] demonstrated adequate levels of protective antibodies in preterm babies
using GSK's hexavalent vaccine. Given the variable results, preterm babies <32 weeks are recommended
to have a booster hepatitis B vaccine dose at 12 months of age in babies with anti-Hbs titres <10 mIU/mL or
unknown. For the pneumococcal conjugate 13-valent vaccine, preterm infants showed a lower antibody
response as compared to term infants but are adequate for protection [48]. As with hepatitis B vaccine, a
booster dose is strongly advised in preterm infants to help maintain protection [49]. Finally, studies on
efficacy of Rotavirus vaccines (both single strain and multi-strain types) have shown good seroconversion
rates in preterm infants [42,50], although the antibody levels were slightly lower in the more preterm
group (27e30 weeks) with the single strain vaccine. Multi-strain vaccine use in preterm infants between
25 and 36 weeks GA decreased rotavirus gastroenteritis of any severity by 73% and hospitalisation and
emergency department visits by 100% [50]. No significant side effects were reported in these studies.
Given the efficacy and safety of rotavirus vaccine in preterm infants, a small window for immunisation
(6e24 weeks), it is prudent to commence rotavirus in preterm infants during the neonatal period.
In summary, premature infants should follow the same vaccination schedule used for full-term infants,
without correcting for prematurity and regardless of birth weight. Even though an impaired immune
response can reduce antibody production and cell-mediated immunity, the immune response is high
enough to ensure short- and long-term protection in most premature infants. A brief overview of
commonly used preparations of vaccines in preterm infants during the neonatal period is provided below.
Infanrix hexa
Indication
Primary immunisation against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and.
Haemophilus influenzae type B [27].
Drug type
Vaccine.
Presentation
Pellets in a vial with suspension for injection in a pre-filled syringe.
Dosage/interval
0.5 mL at 6 weeks/2 months, 4 and 6 months of age.
76
Administration
- Shake well, the pre-filled syringe

- Add its contents to the vial of Hib pellet and shake until pellet is completely dissolved
- Administer 0.5 mL of reconstituted suspension by intramuscular injection to the anterolateral
aspect of the thigh
-Administer on the opposite limb to any concurrently administered vaccines (e.g. pneumococcal
vaccine).
Monitoring
-Apnoea and bradycardia is a common adverse effect in premature infants. They need to be
appropriately monitored for up to 48 h
Precautions
- Significant acute illness or fever >38.5

- Immunosuppressed infants, severe thrombocytopenia or bleeding disorder
Adverse reactions
- Local pain, swelling and redness

- Apnoea and bradycardia, particularly in very preterm neonates
- Fever
- Anaphylaxis
Storage
Store between 2 and 8 Celsius. Freezing destroys the vaccine. Protect from light.
Stability
After reconstitution, the vaccine should be injected promptly. However, the vaccine may be kept for
up to 8 h at room temperature.
Special comments
-Do not give INFANRIX hexa at birth.

-The first dose of INFANRIX hexa can be given at 6 weeks of age due to the high morbidity and
occasional mortality associated with pertussis in very young infants. If the first dose is given at
weeks of age, the next scheduled doses should still be at 4 and 6 months.
-Paracetamol may be prescribed for a fever >38.5 .
Pneumococcal vaccine - prevanar 13
Indication
Primary immunisation against pneumococcal disease in infants [27].
Drug type
Vaccine. Conjugated pneumococcal vaccine composed of pneumococcal serotypes 1, 3, 4, 5, 6A, 6B,
7F, 9V, 14, 18C, 19A, 19F and 23F each conjugated to CRM197 carrier protein.
77
Presentation
Suspension in pre-filled syringe.
Dosage/interval
- 0.5 mL at 6 weeks/2 months, 4 and 6 months of age

- A booster dose at 12 months is recommended in preterm infants <28 weeks
Administration
- Shake syringe vigorously immediately prior to use to obtain a homogeneous, white suspension
- Administer 0.5 mL of reconstituted suspension by intramuscular injection to the anterolateral
aspect of the thigh
- Administer on the opposite limb to any concurrently administered vaccines (e.g. Infanrix hexa).
Monitoring
-Monitor for local swelling or erythema

- Monitor for fever >38.5
Precautions
- Significant acute illness or fever >38.5

- Immunosuppressed infants, severe thrombocytopenia or bleeding disorder
Adverse reactions
- Local pain, swelling and redness

- Fever
-Anaphylaxis
Storage
Store between 2 and 8 Celsius. Do not freeze.
Stability
Vaccine should be injected promptly. However, the vaccine may be kept for up to 8 h at room
temperature.
Special comments
-There are two different types of pneumococcal vaccines e pneumococcal conjugate vaccines and
pneumococcal polysaccharide vaccine. The conjugate vaccine is preferred in young infants,
including preterms due to better immunogenicity
-Prevanar 13 conjugated vaccine is the most used pneumococcal vaccine in preterm babies in
countries like Australia, UK and the United States.
Rotavirus vaccine- rotarix
Indication
Primary immunisation of infants against rotavirus gastroenteritis [27].
78
Schedule Age limit for first dose Age limit for second dose Minimum interval between doses
2 oral doses (1.5 mL/dose) 6e14 weeks 14e24 weeks 4 weeks
Drug type
Vaccine.
Presentation
1.5 mL oral suspension in an oral applicator with plunger stopper.
Dosage/interval
- 1.5 mL orally
- 2-dose course administered with 2- and 4-month immunisations
Administration
- Oral: Administer entire applicator or dosing tube content on the inside of cheek with child in
reclining position
- Gastric tube: For infants who cannot take the vaccine orally, it can be administered through a gastric
tube; flush with air to clear the tube
- Can be given with or without feeds
Monitoring
-Monitor for diarrhoea
Precautions
- Conditions predisposing to severe gastroenteritis (for e.g. Hirschsprungs, short gut syndrome)
- Severe acute gastroenteritis, illness or fever >38
Adverse reactions
- Diarrhoea and vomiting

- Intussusception
Storage
Store between 2 C and 8 C. Do NOT freeze as this reduces potency. Storage above or below the
recommended temperature may decrease potency.
Special comments
- As discussed above, preterm infants should receive vaccine at chronological age. If standard infection
control precautions are maintained and the infant is medically stable, vaccination should not be
delayed, as the delay would result in an infant being beyond the upper age limit for vaccination
- Rotavirus vaccine can be given at any time before or after BCG vaccine
-Co-administration with other routine infant immunisation does not affect immune responses.
Contraindications to preterm vaccination
- Anaphylaxis or hypersensitivity to previous dose or vaccine component

- As a live vaccine, rotavirus is contraindicated in severe immunodeficiencies
79
Novel approaches to neonatal immunisation
As discussed previously, there are several advantages to vaccinating infants during the neonatal
period. Equally, there are several challenges to neonatal immunisation related to deficiencies in their
immune responses. Many novel approaches are being explored to overcome these challenges [19].
Animal studies have suggested that a key requirement for the induction of an effective neonatal
adaptive response is the entrance of antigen into the cytoplasm of APC. Cytoplasmic delivery of anti-
gens may enhance neonatal immune responses by potentially blunting the effect of maternal anti-
bodies. This has been studied using certain DNA vaccines [51] or attenuated strain of the intracellular
bacterium Listeria monocytogenes [52].
Another approach to boost response to vaccination in neonates is to develop an effective Th1-
inducing adjuvant. Alum is currently the only licenced adjuvant in neonate despite studies showing
limited Th1 stimulation. Certain oil in water-based emulsions (MF59) have shown promising results in
mice [53]. Exogenously administered co-stimulatory signals like IL2 and toll-like receptor agonists can
enhance the activity of cytotoxic and Th1-type T cells improving the vaccine response [54,55].
Mucosal administration of vaccines have also been studied as a number of pathogens causing severe
disease in early infancy are mucosally transmitted (rotavirus, respiratory syncytial virus (RSV), polio,
non-typable Salmonella spp. and enterotoxic Escherichia coli). These vaccines may also stimulate
secretory IgA antibodies in addition to IgG and T-cell response [6].
All novel neonatal vaccines described above have been trialled in animals. They need to undergo
rigorous safety evaluations and clinical studies in humans.
Summary
Newborn vaccination has both practical and immunological advantages. Many vaccines such as
BCG, oral polio and hepatitis B are currently administered successfully worldwide. There remain
several challenges to immunisation against other pathogens in this high-risk group. Novel techniques
to optimise antigen-adjuvant combination to activate APCs and potentiate innate response, thereby
promoting Th1 response can help circumvent some of these challenges.
Practice points
- Effective neonatal vaccination can significantly reduce global infant morbidity and mortality.
- Three vaccines are currently administered in the newborn period- BCG, Oral polio and hep-
atitis B.
- Preterm infants should receive vaccines according to the recommended schedule at their
chronological age, without correction for prematurity.
- Novel vaccination strategies show promise against several pathogens, but need to undergo
rigorous clinical studies in humans.
Research agenda
- Maternal vaccination for agents such as group B streptococcus, RSV and pertussis for ben-
efits in newborn.
- Human trials on the efficacy and safety of novel vaccination strategies, including delivery and/
or adjuvants.
80
Declaration of competing interest
The author has no conflicts of interest.
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Best Practice & Research Clinical Obstetrics and Gynaecology 76 (2021) 66e82

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Vaccinations in the newborn

Neonatal immunity and challenges to vaccination

Vaccines given at birth

- In newborns and infants <12 months of age, the dose is 0.05 mL

combined immunodeﬁciency, chronic granulomatous disease and the acquired immunodeﬁciency

-Shelf life is 2 years

The ensuing discussion will focus on Engerix B paediatric formulation [25].

-Postpone vaccination in signiﬁcant acute illness or fever >38.5 C

-Soreness at the injection site is common

-Store between 2 C and 8 C. Do NOT freeze as this reduces potency

Oral polio vaccine

-OPV must be administered orally.

-No immediate monitoring is necessary

- OPV must not be injected

-Long term storage is recommended at 20 C in a deep freezer

Immunisation in preterm infants

- Shake well, the pre-ﬁlled syringe

- Signiﬁcant acute illness or fever >38.5

- Local pain, swelling and redness

-Do not give INFANRIX hexa at birth.

Pneumococcal vaccine - prevanar 13

- 0.5 mL at 6 weeks/2 months, 4 and 6 months of age

-Monitor for local swelling or erythema

- Signiﬁcant acute illness or fever >38.5

- Local pain, swelling and redness

Rotavirus vaccine- rotarix

2 oral doses (1.5 mL/dose) 6e14 weeks 14e24 weeks 4 weeks

-Monitor for diarrhoea

- Diarrhoea and vomiting

Contraindications to preterm vaccination

- Anaphylaxis or hypersensitivity to previous dose or vaccine component

Novel approaches to neonatal immunisation

Declaration of competing interest

The author has no conﬂicts of interest.

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