REVIEW

C URRENT
OPINION Vaccination updates and special considerations for
systemic lupus erythematosus patients
Jammie Law, Cristina Sorrento and Amit Saxena

Purpose of review
We review the latest guidelines and note special considerations for systemic lupus erythematosus (SLE)
patients when approaching vaccination against SARS-CoV-2, influenza, pneumococcus, herpes zoster, and
potentially respiratory syncytial virus (RSV) vaccine in the future.
Recent findings
SLE patients have unique infectious risks due to newer treatments and the nature of the disease itself. It is
important to balance the benefit of additional protective immunity from updated vaccines against the
possible risk of disease activity exacerbations.
Summary
It is important to continuously evaluate the safety and immunogenicity of updated vaccines specifically for
SLE patients. Additionally, the newly approved RSV vaccine should be considered for this population to
reduce severe respiratory illness.
Keywords
Systemic lupus erythematosus, vaccination, SARS-CoV2, influenza, pneumococcus, herpes zoster, RSV

INTRODUCTION CURRENT COVID VACCINATION

Systemic lupus erythematosus (SLE) is a multisystem
disease of immune dysregulation that can increase
risk of infection. Mechanisms of immune dysregu-
lation that may predispose SLE patients to infection
include impaired neutrophil chemotaxis, lympho-
penia, decreased T cell cytotoxic activity, and
hypocomplementemia due to immune complex for-
mation [1]. Patients often require immunosuppres-
sion, which can further enhance this risk [2,3].
There have been considerable advances in vaccines
and treatments for SLE, but concerns regarding vac-
cination in SLE patients remain [4]. Notably, treat-
ments specific to SLE that target the type I interferon
pathway, such as anifrolumab, have been associated
with an increased risk of viral infections. It is impor-
tant to continuously evaluate the safety and immu-
nogenicity of updated vaccines specifically for SLE
patients, due to infectious risk that may differ from
other autoimmune diseases [5]. We review the latest
guidelines and note special considerations for SLE
patients when approaching vaccination against
SARS-CoV-2, influenza, pneumococcus, herpes zos-
ter, and potentially respiratory syncytial virus (RSV)
in the future.
RECOMMENDATION FOR PATIENTS WITH
RHEUMATIC DISEASE
Patients with SLE and other rheumatic diseases are at
risk for severe coronavirus disease. The original 2021
monovalent vaccines were authorized for emer-
gency use with significant success, but breakthrough
SARS-CoV-2 infections were observed particularly in
those taking mycophenolate or B-cell depleting
therapy [6,7]. The American College of Rheumatol-
ogy (ACR) formed a task force to provide guidance
for COVID vaccination, although recommendations
predate newer escape variants [8]. While vaccination
ideally occurs during well controlled disease,
COVID vaccination is recommended regardless of
disease activity, theoretical risk of flare, minor
Division of Rheumatology, Department of Medicine, New York University
Grossman School of Medicine, New York, New York, USA
Correspondence to Jammie Law, MD, New York University Grossman
School of Medicine, New York, NY 10016, USA. Tel: +1 646 501 4114;
e-mail: jl3368@rwjms.rutgers.edu
Curr Opin Rheumatol 2024, 36:148–153
DOI:10.1097/BOR.0000000000000992

www.co-rheumatology.com Volume 36  Number 2  March 2024

Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.


KEY POINTS
 SLE patients are at increased risk of vaccine-
preventable infections.
 An additional third dose of COVID vaccination appears
to offer additional immunity and protection against
disease in SLE.
 Prior data for pneumococcal vaccination in SLE may
suggest poor immunogenicity even with a prime- boost
strategy. The benefit of a single dose of PCV20 vaccine
remains to be elucidated, but vaccination remains
recommended in patients receiving
immunosuppressive medications.
 Certain targeted treatments specific to SLE may
increase risk of viral infections, which highlights the
importance of early herpes zoster subunit vaccine and
high dose quadrivalent influenza or adjuvanted
influenza vaccination in this population.
 SLE patients may be an appropriate demographic to
consider for RSV vaccination in the future given the use
of immunosuppressant therapies that may impair
viral defense.
adverse event with previous doses, or prior SARS-
CoV-2 infection. One or two supplemental vaccine
doses were recommended for patients who were not
expected to mount an adequate response to the
original vaccines. In 2022, a bivalent vaccine was
released targeting the Omicron BA.4 and BA.5 var-
iants. As of September 2023, an updated monova-
lent vaccine targeting the XBB 1.5 variant was
recommended in the United States even in patients
with prior vaccine history [9]. There is no additional
task force guidance regarding these newer vaccines
for SLE patients to date [8,10].
SPECIAL IMPLICATIONS OF COVID
VACCINATION FOR SYSTEMIC LUPUS
ERYTHEMATOSUS PATIENTS
Initial studies on the 2021 original COVID vaccine
series administered to SLE patients demonstrated
clinical efficacy with impaired but generally suffi-
& &
cient immunogenicity [11,12 ]. Despite theoretical
risks, patient concerns, and case reports, vaccination
rarely precipitated severe flares in larger studies
&
[12 ,13–18].
Variable reports show impaired immune
responses in SLE patients on belimumab, tacroli-
mus, mycophenolate, higher glucocorticoid doses,
and more than one immunosuppressant. Holding
mycophenolate for 1 week after vaccination signifi-
cantly increased postvaccine IgG levels without
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Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Vaccination updates and special considerations Law et al.
&
leading to flares [19,20 ]. Longer lasting immuno-
genicity after the 2021 original vaccine series
&
may be impaired in SLE patients [21 ], but an addi-
tional dose decreased subsequent SARS-CoV-2
&
infections [22 ]. A third dose of vaccination for
SLE patients augmented antibody and cellular
immunity responses, even in the setting of belimu-
&
mab [23,24 ,25,26]. Overall data support the
prior recommendation of additional doses of
COVID vaccination. Further studies on the updated
2023 monovalent vaccine in SLE patients would
be beneficial to identify additional safety markers
and the immunogenicity of subsequent doses.
CURRENT INFLUENZA VACCINATION
RECOMMENDATION FOR PATIENTS WITH
RHEUMATIC DISEASE
Influenza may cause serious illness in patients with
rheumatic disease. Quadrivalent vaccines protect
against four different strains: influenza A (H1N1),
influenza A (H3N2), and two influenza B viruses.
The ACR and European Alliance of Associations for
Rheumatology (EULAR) strongly recommend influ-
enza vaccination for patients with rheumatic dis-
&
ease including SLE [27 ,28]. Notably, the ACR
conditionally recommends the high-dose or adju-
vanted influenza vaccination over the standard
dose vaccine for adult patients more than 18 years
and less than 65 years who are taking immunosup-
pressive medication. Standard dose influenza vac-
cination is still recommended if barriers exist for
patients to receive high dose or adjuvanted influ-
enza vaccines.
Current ACR guidelines also emphasize the
importance of timely influenza vaccination over
holding most immunosuppressive medications,
and conditionally recommend administering the
influenza vaccination on schedule for patients
who are taking rituximab (delaying dosing by
2 weeks if disease activity allows). There are con-
cerns that methotrexate may blunt the immuno-
genicity of the influenza vaccine. The ACR
conditionally recommends holding methotrexate
for 2 weeks afterwards, though holding for 1 week
compared to 2 weeks after vaccination may be
noninferior [29,30 ]. However, this was studied
in rheumatoid arthritis patients and studies for
SLE patients have not been reported. Finally,
ACR conditionally recommends administering
the influenza vaccination even in patients taking
an equivalent of prednisone at least 20 mg
daily. This recommendation focusing on glucocor-
ticoid doses should be considered for SLE
patients being treated for moderate to severe organ
manifestations.
www.co-rheumatology.com 149
Immunopathogenesis and treatment of autoimmune diseases
SPECIAL IMPLICATIONS OF INFLUENZA
VACCINATION IN SYSTEMIC LUPUS
ERYTHEMATOSUS
The safety, immunogenicity, and clinical efficacy of
earlier standard dose influenza vaccination is well
established in SLE patients [31–37]. Immunogenic-
ity is lower in SLE patients with the standard vacci-
nation, but additional booster vaccination does not
improve immunogenicity [32,37]. The ACR recom-
mendation for high dose quadrivalent or adju-
vanted influenza vaccination may raise concern
about potential SLE flares. The high-dose influenza
vaccine contains four times the amount of antigen
as the standard dose. The adjuvanted vaccine con-
tains an MF59 adjuvant, which accentuates the
immune response. There are currently no safety
studies in SLE patients with these vaccines, but
high-dose quadrivalent influenza vaccine and adju-
vanted trivalent vaccines have higher immunoge-
nicity in other immunocompromised groups [38–
40]. Rheumatoid arthritis patients were more likely
to seroconvert with high-dose trivalent vaccine
compared to standard dose quadrivalent vaccine
[41]. Additionally, this study showed no increased
disease activity with either vaccine, which is reassur-
ing to consider for SLE patients.
Newer biological treatments for SLE have
reported higher incidence of viral infections includ-
&
ing influenza [42,43,44 ]. In long-term safety studies
of anifrolumab (years 2–4), 5.8% of SLE patients had
influenza infections compared to the placebo group
&
(1.8%) [44 ]. Given the unique risk posed by new
therapies affecting the type I interferon pathway,
high-dose or adjuvanted influenza vaccines may be
prudent for SLE patients. There is currently a pilot
study examining the impact of anifrolumab on
developing neutralizing antibodies to quadrivalent
vaccine in moderate to severe SLE [45].
CURRENT PNEUMOCOCCAL
VACCINATION RECOMMENDATION FOR
PATIENTS WITH RHEUMATIC DISEASE
Several pneumococcal vaccinations are used in the
general population including patients with rheu-
matic disease. In the United States, pneumococcal
vaccination consists of a two-dose prime-boost
approach with a pneumococcal conjugate vaccine
(PCV 15) followed by a pneumococcal polysacchar-
ide vaccine (PPSV23). PCV20 is the newest conju-
gate vaccine that may be administered as a single
dose and provides durable protection through T cell
mediated immunity.
There is a strong recommendation to consider
pneumococcal vaccination in patients with rheu-
&
matic disease including SLE [27 ,28,46]. The
150 www.co-rheumatology.com
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guidelines for unvaccinated patients who are over
65 and SLE patients between 18 and 65 years old
who are on immunosuppression are the same; they
should receive PCV15 followed by PPSV23 or a
single dose of PCV20. If a patient previously received
both PCV13 and PPSV23, a dose of PCV20 or a
second dose of PPSV23 completes vaccination until
age 65. If a patient received only PPSV23, either
PCV15 or PCV20 completes the vaccine series. If
patients previously received only PCV13, patients
may either obtain PCV20 or two doses of PPSV23
separated 5 years apart or one dose of PPSV23 and
one dose of PCV20 separated 5 years apart. When a
second PPSV23 dose is used, no additional pneumo-
coccal vaccines are recommended until age 65.
When PCV20 is used, the vaccine series is complete
until age 65 [47].
SPECIAL IMPLICATIONS OF
PNEUMOCOCCAL VACCINATION IN
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE patients are at risk of invasive pneumococcal
infections [48,49], but patients identify concerns
about disease flares or side effects as barriers to
receiving pneumococcal vaccinations [50].
Although limited, a study of PPSV23 vaccination
in 75 SLE patients, including 13% with severe SLE,
reported no disease exacerbations and lower rates of
respiratory illness [51]. While a single dose of PCV20
may decrease the complexity of pneumococcal vac-
cination, there are currently no safety or immuno-
genicity studies of PCV20 in SLE patients.
Prior studies have used earlier conjugate vac-
cines or polysaccharide vaccines alone and are dif-
ficult to compare head-to-head, but may suggest
decreased immunogenicity in this population
[52–55]. Caution should be used when interpreting
seroconversion in patients vaccinated with earlier
pneumococcal vaccines given the need to evaluate
response to individual serotypes [56]. Regarding the
recommendation for a prime-boost strategy, a small
cohort of SLE patients showed that PCV13 followed
by PPSV23 had better immunogenicity compared to
&
the alternate sequence [57 ]. However, long-term
immunity was not sustained with the same prime-
boost vaccination strategy, which may correlate
with certain baseline immunoglobulin G serotype
levels [58,59].
Like other vaccinations, there is concern that B
cell depleting biological therapy may impact the
immunogenicity of pneumococcal vaccination in
SLE patients [60]. This effect was not observed in
studies with belimumab, although the prime-boost
approach was not utilized limiting its current applic-
ability to PCV20 [60,61]. Although SLE patients were
Volume 36  Number 2  March 2024

not represented, patients on rituximab had
impaired immunogenicity in a study with earlier
versions of PCV followed by PPSV23 [62]. For
patients with rheumatic disease on rituximab, the
ACR conditionally recommends delaying nonlive
attenuated vaccinations, such as pneumococcal vac-
cination, until the next dosing cycle and holding
rituximab for another 2 weeks after vaccination
&
[27 ].
CURRENT ZOSTER VACCINATION
RECOMMENDATIONS FOR PATIENTS
WITH RHEUMATIC DISEASE
Herpes zoster infection remains a significant concern
for patients with rheumatic disease including SLE.
Previously, a live zoster vaccine was available,
although its use was limited. Approved in 2021, the
HZ subunit recombinant vaccine is a two-dose vaccine
that contains varicella zoster virus glycoprotein IgE
with adjuvant AS01B to improve immunogenicity.
Due to the high level of immune reactivity in
SLE, there is a theoretical risk of concurrent
enhanced autoantigen presentation to T cells and
increased adaptive immune responses secondary to
adjuvant administration. In the herpes zoster sub-
unit vaccine phase III studies, the incidence of
immune-mediated diseases, inclusive of autoim-
mune and other inflammatory or neurologic disor-
ders, was low and similar to those receiving herpes
zoster subunit vaccine and placebo (1.2 vs. 1.3%)
[63,64]. Patients with autoimmune diseases were
not explicitly excluded from the studies, but recruit-
ment was limited since immunosuppressive medi-
cation use was excluded.
The ACR strongly recommends administering
the herpes zoster subunit recombinant vaccine to
patients at least more than 18 years old with rheu-
matic disease taking immunosuppressive medica-
tions, although this recommendation was made
based on immunogenicity data in patients of other
immunocompromised groups [65–67].
SPECIAL IMPLICATIONS OF ZOSTER
VACCINATION IN SYSTEMIC LUPUS
ERYTHEMATOSUS
SLE patients are at a higher risk of herpes zoster
infections and the use of certain immunosuppres-
sant therapy such as anifrolumab may further
increase this risk [68,69]. Anifrolumab is a mAb
blocking the antiinterferon 1 signal, a key mediator
in viral defense. Pooled analysis of the phase II and
III pivotal trials of anifrolumab found the incidence
of herpes zoster was 6.1% in the treatment arm
compared to 1.3% in the standard of care arm
1040-8711 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Vaccination updates and special considerations Law et al.
[70]. Herpes zoster was more frequent in anifrolu-
mab patients that were also receiving an additional
immunosuppressant treatment (9.8 vs. 3.2%). In
extension studies, herpes zoster rates were similar
in anifrolumab patients as compared to standard of
care patients (8.9 vs. 6.3% in years 2–4), indicating
the baseline risk of herpes zoster infection in all SLE
&
patients [44 ].
A pilot study of the previously available live
attenuated zoster vaccine in SLE patients did not
show increased disease activity. Although cell-medi-
ated immunity was lower in SLE patients, the pro-
portion of individuals who mounted an immune
response was similar to controls [71]. Thus far, there
are no prospective trials evaluating the safety and
efficacy of the herpes zoster subunit vaccine in SLE
patients. However, in a broad retrospective study of
patients with autoimmune diseases including SLE,
no significant difference in disease flare following
&
herpes zoster subunit vaccine was observed [72 ].
Other retrospective studies of herpes zoster subunit
vaccine that included SLE patients have shown mild
flares [73,74]. Several prospective studies (USA,
Hong Kong, Korea) are actively evaluating the safety
and immunogenicity of the herpes zoster subunit
recombinant vaccine in SLE patients [75].
RSV VACCINATION IN SYSTEMIC LUPUS
ERYTHEMATOSUS: ON THE HORIZON?
RSV causes respiratory tract illness and hospitaliza-
tion for children, older adults, and the immuno-
compromised [76–78]. The FDA recently approved
the first RSV vaccination for individuals 60 years or
older [79,80]. Given its novelty, there are currently
no specific recommendations for RSV vaccination
in SLE patients. The RSV vaccine is a single-dose
adjuvanted (AS01E) recombinant vaccine of prefu-
sion F protein. High risk comorbidities that may be
considered for the RSV vaccine include cardiopul-
monary disease, moderate or severe immunocom-
promise, diabetes, neurologic or neuromuscular,
kidney, liver, or hematologic disorders [81]. Accord-
ingly, SLE patients may be an appropriate demo-
graphic for early vaccination in the future given the
increasing use of type I interferon directed therapies
that may impair viral defense [44 ].
&
CONCLUSION
Vaccination remains an important tool to protect
SLE patients. Prior research may suggest that SLE
patients have lower immunogenicity to standard
vaccines compared to healthy controls. This lower
immunogenicity may be influenced by treatments
needed to control disease activity and prevent organ
www.co-rheumatology.com 151
Immunopathogenesis and treatment of autoimmune diseases
damage. While there is a trend to recommend
updated vaccines to improve immunogenicity, stud-
ies specific to SLE populations should be performed
to elucidate safety. With new targeted therapies for
SLE such as anifrolumab available, minimizing risk
of infection with vaccinations should be a priority.
Acknowledgements
None.
Financial support and sponsorship
A.S. has received consulting fees with BMS, Astra Zeneca,
Kezar, GSK and Eli Lilly.
Conflicts of interest
None.
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