- Statement on the antigen composition of COVID-19 vaccines
The WHO Technical Advisory Group on COVID-19 Vaccine Composition
(TAG-CO-VAC) continues to meet regularly to assess the implications of
SARS-CoV-2 evolution for COVID-19 vaccine antigen composition and advise
WHO on whether changes are needed to the antigen composition of future
COVID-19 vaccines.
In April 2023, the TAG-CO-VAC indicated
that the advisory group would convene at least twice in 2023: once in
May 2023 and again, approximately 6 months later. At each meeting,
recommendations to either maintain current vaccine composition or to
consider updates will be issued. This frequency of evidence review by
the TAG-CO-VAC is based on the kinetics of vaccine-derived immunity and
the need for continued monitoring of the evolution of SARS-CoV-2, and
will be adjusted if and as necessary. The TAG-CO-VAC met on 11-12 May
2023 to review the genetic and antigenic evolution of SARS-CoV-2, the
performance of currently approved vaccines against circulating
SARS-CoV-2 variants and the implications for COVID-19 vaccine antigen
composition.
As previously stated by the TAG-CO-VAC, the objective of an update to COVID-19 vaccine antigen composition is to enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants.
This statement and the recommendation for change is intended for all
vaccine manufacturers and is intended to inform future formulations of
COVID-19 vaccines.
The TAG-CO-VAC recognizes and reiterates
that currently approved COVID-19 vaccines, including those based on the
index virus, continue to provide substantial protection against severe
disease and death, which is the primary objective for COVID-19
vaccination. Currently approved COVID-19 vaccines should continue to be
used in accordance with the current WHO SAGE Roadmap,
published in April 2023. Notwithstanding the protection against severe
disease, protection against symptomatic disease is limited and less
durable. New formulations of COVID-19 vaccines are needed to improve
protection against symptomatic disease.
Evidence reviewed
The
published and unpublished evidence reviewed by the TAG-CO-VAC included:
(1) SARS-CoV-2 evolution, including genetic and antigenic
characteristics of earlier and current SARS-CoV-2 variants, including
XBB.1 descendent lineages, and its impact on cross-neutralization and
cross-protection following vaccination and/or infection; (2) Vaccine
effectiveness (VE) of currently approved vaccines during periods of
XBB.1 descendant lineage circulation; (3) Antigenic cartography
analyzing antigenic relationships of SARS-CoV-2 variants using naïve
animal sera and human sera following vaccination and/or infection; (4)
Preliminary preclinical data on immune responses in animal models,
following infection with XBB.1 descendent lineages; (5) Preliminary
preclinical immunogenicity data on the performance of candidate vaccines
with updated antigens (data not shown); and (6) B cell memory responses
following vaccination and/or infection.
Further details on
the publicly available data reviewed by the TAG-CO-VAC can be found in
the accompanying data annex. Unpublished and/or confidential data are
not shown.
The TAG-CO-VAC acknowledges the limitations of the available data:
- While
the trajectory of further SARS-CoV-2 evolution indicates that XBB will
likely be the progenitor of SARS-CoV-2 variants in the near term, the
timing, specific mutations and antigenic characteristics, and the
potential public health risks of future variants remain unknown;
- Data
on cross-reactivity (breadth) of immune responses elicited by currently
circulating SARS-CoV-2 variants are limited. The majority of the
available clinical and preclinical data are on the recent variants XBB.1
or XBB.1.5, but there is minimal information on other current variants of interest or variants under monitoring;
- Data on immune responses over time following infection with currently circulating SARS-CoV-2 variants are limited;
- Though
neutralizing antibodies titers have been shown to be important in
protection from SARS-CoV-2 infection and in estimates of vaccine
effectiveness, there are multiple layers of immune protection elicited
by infection and/or vaccination. Data on the immune response specific
for XBB.1 descendent lineages are largely restricted to neutralizing
antibodies and are limited for other aspects of the immune response,
including cellular immunity;
- Data on the protection conferred by
hybrid immunity (i.e. combination of infection- and vaccination-induced
immunity) are largely derived from populations that predominantly
received an mRNA booster dose;
- Data on VE of current COVID-19
vaccines, including index-virus based and bivalent mRNA vaccines,
against XBB descendent lineages are limited and estimates during periods
of XBB.1 descendant lineage circulation are only available for mRNA
vaccines;
- Data on candidate vaccines that include an XBB.1 descendent lineage are limited to animal models.
A summary of available evidence and the recommendations that follow were discussed by the TAG-CO-VAC and provided to WHO.
Summary of available evidence
- In
the fourth year of the pandemic, there is high seroprevalence in the
global population as a result of vaccination and/or infection, and
immunological profiles against SARS-CoV-2 are highly heterogeneous (i.e.
individuals have been infected with different variants and/or
vaccinated using a variety of vaccine platforms).
- There
continues to be substantial genetic and antigenic evolution of the spike
protein of SARS-CoV-2, and the evolutionary trajectory continues to
diverge from the index virus. Despite increasing gaps in genomic
surveillance globally, the available sequencing data indicates that the
index virus and other early variants (e.g., Alpha, Beta, Gamma and
Delta) are no longer detected in humans.
- As of May 2023, the XBB.1 descendent lineages currently predominate globally (i.e., XBB.1.5, XBB.1.16, XBB.1.9).
- As described in the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution XBB.1.5 Updated Risk Assessment and the XBB.1.16 Initial Risk Assessment,
XBB descendent lineages, including XBB.1.5 and XBB.1.16, are highly
immune evasive, with XBB.1.5 being one of the SARS-CoV-2 variants with
the greatest magnitude of immune escape from neutralizing antibodies to
date.
- Estimates of VE against currently circulating SARS-CoV-2
variants, including XBB.1 descendent lineages, are very limited in terms
of the number of studies, vaccine products evaluated, and populations
assessed; some studies show similar VE against BA.5 descendent and XBB.1
descendent lineages, while others suggest reduced VE during periods of
predominance of XBB.1 descendent lineages.
- Sera from individuals
who have received two, three or four doses of index virus-based
vaccines, or a booster dose of a bivalent (BA.1- or BA.4/5- containing)
mRNA vaccine show substantially lower neutralizing antibody titers
against XBB.1 descendent lineages, as compared to titers specific for
the antigens included in the vaccine. Individuals with hybrid immunity
due to any SARS-CoV-2 infection show higher neutralizing antibody titers
against XBB.1 descendent lineages as compared to responses from
vaccinated individuals who had no evidence of infection.
- There is in vitro
evidence that immune imprinting, which is a phenomenon in which B cell
memory recall responses towards previously encountered antigen reduce
the response to new antigens, may be occurring. However, based on
observational epidemiological studies to date, the clinical impact
remains unclear.
- Preclinical data shared confidentially with the
TAG-CO-VAC by vaccine manufacturers show that vaccination with XBB.1
descendent lineage-containing candidate vaccines (including XBB.1.5)
elicits higher neutralizing antibody responses to currently circulating
SARS-CoV-2 variants, compared to responses elicited by currently
approved vaccines.
Recommendations for updates to COVID-19 vaccine antigen composition
There
is ongoing and considerable genetic and antigenic evolution of
SARS-CoV-2, high seroprevalence and heterogeneous population immunity to
SARS-CoV-2. As current WHO SAGE policy specifies, vaccination
programmes should continue to complete the primary series and booster
dose(s) for high priority and medium priority groups. Furthermore, the
WHO Global COVID-19 Vaccination Strategy, published in July 2022, also calls for vaccines with improved durability and breadth of protection.
Updates to vaccine antigen composition may enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants, consistent with the previous statement by the TAG-CO-VAC published in June 2022.
As
of May 2023, XBB.1 descendent lineages predominate SARS-CoV-2
circulation globally. In order to improve protection, in particular
against symptomatic disease, new formulations of COVID-19 vaccines
should aim to induce antibody responses that neutralize XBB descendent
lineages. One approach recommended by TAG-CO-VAC is the use of a monovalent XBB.1 descendent lineage, such as XBB.1.5
(e.g., hCoV-19/USA/RI-CDC-2-6647173/2022, GenBank: OQ054680.1, GISAID:
EPI_ISL_16134259 or WHO Biohub: 2023-WHO-LS-01, GenBank: OQ983940,
GISAID EPI_ISL_16760602) as the vaccine antigen. Given the small genetic
and antigenic differences from XBB.1.5, XBB.1.16 (e.g.,
hCoV-19/USA/MI-CDC-LC1038976/2023, GenBank: OQ931660 GISAID:
EPI_ISL_17619088) may be an alternative. The spike antigens of both of
these lineages are genetically and antigenically very closely related,
with only two amino acid differences between XBB.1.5 and XBB.1.16 (E180V
and T478R). Other formulations and/or platforms that achieve robust
neutralizing antibody responses against XBB descendent lineages can be
considered.
While currently approved COVID-19 vaccines,
including those based on the index virus, continue to provide protection
against severe disease, the TAG-CO-VAC advises moving away from the
inclusion of the index virus in future formulations of COVID-19
vaccines. This is based on the following reasons: the index virus and
antigenically closely related variants no longer circulate in humans;
the index virus antigen elicits undetectable or very low levels of
neutralizing antibodies against currently circulating SARS-CoV-2
variants, including XBB descendent lineages; inclusion of the index
virus in bi- or multivalent vaccines reduces the concentration of the
new target antigen(s) as compared to monovalent vaccines, which may
decrease the magnitude of the humoral immune response; and immune
imprinting due to repeated exposure to the index virus may reduce immune
responses to new target antigen(s).
Further data requirements and considerations
Given
the limitations of the evidence upon which the recommendations above
are derived and that the evolution of the virus is expected to continue,
the TAG-CO-VAC strongly encourages the generation of data on immune
responses and clinical endpoints in humans who receive a COVID-19
vaccine with an updated composition, across different vaccine platforms,
as well as further data on the performance of current COVID-19 vaccines
against circulating SARS-CoV-2 variants. Additionally, the TAG-CO-VAC
continues to encourage the further development of vaccines that enhance
mucosal immunity because they may improve protection against infection
and reduce transmission of SARS-CoV-2, in alignment with the WHO Global COVID-19 Vaccination Strategy,
published in July 2022. Finally, it is imperative for multilateral
organizations, governments and manufacturers to continue collaborating
towards access to currently approved COVID-19 vaccines and to ensure
equitable global access for vaccine(s) with an updated antigen
composition as they become available.
