Individuals with compromised immune systems, whether because of immunodeficiency or
immunosuppressive therapy, are among those most susceptible to COVID-19. In fact,
people who are immunocompromised are doubly susceptible. On the one hand, people who
are immunocompromised are more likely to suffer the gravest consequences of SARS-CoV-2
infection, including severe or fatal disease.1, 2 On the other hand, such individuals
are less likely to mount a sufficient immune response to COVID-19 vaccination.
Although the evidence base is skewed towards mRNA vaccines, the reduced vaccine response
in people who are immunocompromised compared with people who are not immunocompromised
appears to be a general phenomenon across COVID-19 vaccines and vaccine platforms.
In a systematic review, seroconversion rates after two COVID-19 vaccine doses (pooling
across all studies and platforms) were 99% (95% CI 98–100) for people who are not
immunocompromised, 92% (88–94%) for patients with solid cancer, 78% (69–95) for patients
with immune-mediated inflammatory disorders, 64% (50–76) for patients with haematological
cancer, and 27% (16–42) for recipients of transplants.
3
Corroborating these findings, people who are immunocompromised exhibit reduced protection
against symptomatic and severe COVID-19 on the basis of real-world effectiveness data
(available for mRNA and vectored vaccines),4, 5, 6 and make up greater than 40% of
hospitalised breakthrough cases despite representing a much smaller proportion of
the general population.
7
To mitigate the risk of COVID-19 among vaccinated people who are immunocompromised,
countries have increasingly opted to offer these individuals an additional vaccine
dose. As of Oct, 2021, this policy has been recommended by WHO for people who are
moderately or severely immunocompromised.
8
Notably, such policies should be considered separately from those relating to booster
doses—given once an initially sufficient immune response rate in a vaccinated population
has waned over time.
9
Rather, offering additional doses to people who are immunocompromised should be considered
part of an extended primary series that seeks to increase the proportion of individuals
in the population who achieve a sufficient protective immune response to begin with.
Yet the extent to which additional doses enhance protection against COVID-19 among
people who are immunocompromised remains uncertain. With this in mind, we did a rapid
review of the safety, immunogenicity, and efficacy or effectiveness of additional
vaccine doses in people who are immunocompromised, covering articles and preprints
published between July 1, 2020 and Sept 27, 2021. Our aim was to capture emerging
trends within the heterogenous body of available evidence. The primary outcome of
interest was the prevalence of SARS-CoV-2 spike-specific binding antibodies before
versus after a single additional dose of a COVID-19 vaccine with a WHO Emergency Use
Listing (for full literature review methods see appendix pp 1–2).
Overall, we identified 23 eligible studies reporting on a total of 1722 people who
are immunocompromised receiving an additional COVID-19 vaccine dose (median sample
size of 60, IQR 34·5–81·5; for summary and citation details see appendix pp 3–5).
These included two randomised controlled trials and 21 observational studies done
in countries that were early to adopt a policy of offering an additional dose to people
who are immunocompromised.
10
The evidence base is skewed towards mRNA vaccines (exclusively offered in 18 of the
eligible studies), although several studies have explored the potential merits of
a heterologous additional dose (Ad26.COV2.S or ChAdOx1-S) following a two-dose mRNA
primary vaccination series. Study cohorts consisted of patients with solid organ transplants
(13 studies), patients receiving dialysis (five studies), patients with cancer (three
studies), and other groups of people who are immunocompromised (two studies). All
available studies reported on one or more humoral immune response endpoints, with
a subset reporting on cellular immune responses (ten studies) and on safety (17 studies).
The additional dose was administered 1–3 months after completion of the standard primary
vaccination series in 20 of the 21 studies reporting this information. No studies
reported on the efficacy or effectiveness of an additional COVID-19 vaccine dose among
people who are immunocompromised.
Despite significant variation in terms of vaccination schedule, sample timing, and
serological response criteria, several trends are apparent across the included studies.
First, the reactogenicity profile of additional doses in people who are immunocompromised,
where reported, has generally been consistent with that observed for earlier doses
of the vaccine being administered,
11
with no major safety concerns identified. Second, receipt of an additional dose appears
to have a modest additive effect on cumulative immunogenicity, with median antibody
response rates increasing from 41% (IQR 23–58) after the standard primary series to
67% (55–69) after the additional dose among studies with paired data, albeit with
notable variation among patient groups (figure A
). Finally, among individuals with a low or undetectable antibody response after the
standard primary series (an eligibility criterion for several of the included studies),
the additional dose was associated with a median antibody response rate of 44% (IQR
32–55; figure B). Crucially, these data suggest that an additional dose in an extended
primary series does not simply increase an existing antibody response in those who
responded to the primary vaccination series but is capable of inducing a de novo response
in at least a portion of people who are immunocompromised who did not mount a detectable
antibody response after the standard primary series.
Figure
Antibody response rate following an additional COVID-19 vaccine dose in people who
are immunocompromised
(A) Cumulative antibody response rates before and after an additional dose in different
patient subgroups across 13 studies with paired data. Lines link estimates from individual
study populations. The same participants were measured before and after the additional
dose. (B) Antibody response rates following an additional dose among patients with
low or no detectable antibodies after the standard primary series (19 estimates from
17 studies). Note that antibody response criteria and patient characteristics varied
among studies, restricting comparability (see appendix pp 3–5 for details). Estimates
for subgroups receiving mRNA and vectored vaccines were extracted separately where
possible. *Denominator includes patients who did not receive an additional dose but
responded after the primary vaccine series. †Post-vaccination data available for a
subset of the cohort.
These findings must be interpreted with caution given the absence of an established
correlate of initial protection or duration of protection. The significant methodological
variation among studies (especially with respect to antibody response criteria and
characteristics of the patient population; appendix pp 3–5) also represents a notable
limitation of the present review, and probably contributes to the wide variation in
response rates observed. Nonetheless, the benefits of an additional dose as part of
an extended primary series among people who are immunocompromised are likely to outweigh
the risks on the basis of the available data. Despite the imbalance in the evidence
base towards mRNA vaccines, it is reasonable to expect this relative benefit to apply
across other COVID-19 vaccines and vaccine platforms. However, key evidence gaps must
be urgently addressed, including the safety, effectiveness, and duration of protection
provided by one or more additional doses in an extended primary series in people who
are immunocompromised (including specific patient subgroups), especially for vectored,
inactivated, and subunit vaccines for which extensive data are lacking; the relative
benefits of heterologous versus homologous additional doses among people who are immunocompromised;
the optimal timing of the additional dose; and the effectiveness of standard and extended
primary vaccine series among subgroups of people who are immunocompromised that are
under-represented in the existing literature, including people living with HIV that
is not well-controlled.
Our findings also highlight the need for continued caution among people who are immunocompromised
while SARS-CoV-2 transmission remains high globally. Many people who are immunocompromised
with severe immunosuppression are likely to remain susceptible to COVID-19 even after
an additional dose. Indeed, cumulative antibody response rates after the additional
dose in people who are immunocompromised typically fall some way short of the response
rates observed after a standard primary series in people who are not immunocompromised.
Accordingly, additional protective measures within the households and care facilities
of people who are immunocompromised, including vaccination of close contacts as well
as other public health and social measures, will be crucial to reduce the risk of
transmission to this susceptible population.
The authors acknowledge the contributions of all members of the WHO Strategic Advisory
Group of Experts (SAGE) on Immunization and the SAGE Working Group on COVID-19 Vaccines.
EPKP is a consultant for the SAGE Working Group on COVID-19 vaccines. SD, MM, KLO’B,
JH, and AW-S are staff of WHO. The authors alone are responsible for the views expressed
in this article and they do not necessarily represent the views, decisions, or policies
of the institutions with which they are affiliated. SK and HN are members of SAGE.
DCK is a member of the SAGE Working Group on COVID-19 vaccines.