Statement on the antigenic composition of the vaccine against COVID-19

Key points

• SARS-CoV-2 continues to circulate and evolve with important genetic and antigenic evolution of the spike protein.
• The goal of updating the antigen composition of the COVID-19 vaccine is to improve vaccine-induced immune responses to circulating SARS-CoV-2 variants.
• Because the virus is expected to continue to evolve from JN.1, TAG-CO-VAC advises against its use monovalent JN.1 lineage as an antigen in future formulations of vaccines against COVID-19.
• In accordance with the WHO SAGE policy, vaccination programs should continue to use any COVID-19 vaccine on the WHO list for emergency use or a prequalified vaccine, and vaccination should not be delayed pending access to updated vaccines.

WHO Technical advisory group for the composition of the vaccine against COVID-19 (TAG-CO-VAC) meets regularly to assess the impact of SARS-CoV-2 developments on the effectiveness of approved vaccines against COVID-19. This includes face-to-face meetings approximately every six months to determine the implications of the evolution of SARS-CoV-2 on the antigenic composition of the COVID-19 vaccine and to advise WHO on whether changes to the antigenic composition of future COVID-19 vaccines are needed. The evidence review conducted by TAG-CO-VAC twice a year is based on the need to continuously monitor the evolution of SARS-CoV-2 and the kinetics and protection of vaccine-derived immunity.

In May 2023, TAG-CO-VAC recommended the use of a monovalent XBB.1 progeny, such as XBB.1.5, as a vaccine antigen. In December 2023, TAG-CO-VAC advised to maintain the use of a monovalent XBB.1 progeny, such as XBB.1.5, as a vaccine antigen. Several manufacturers (using mRNA, protein, and viral vector vaccine platforms) have developed monovalent XBB.1.5-formulated COVID-19 vaccines that have been approved for use by regulatory authorities and introduced into COVID-19 vaccination programs in some countries. Previous TAG-CO-VAC statements can be found at WHO site.

TAG-CO-VAC reconvened on 15 and 16 April 2024 to review the genetic and antigenic evolution of SARS-CoV-2; immune responses to SARS-CoV-2 infection and/or vaccination against COVID-19; the effect of currently approved vaccines against circulating variants of SARS-CoV-2; and implications for the antigen composition of the vaccine against COVID-19.

Evidence reviewed

Published and unpublished evidence reviewed by TAG-CO-VAC included: (1) genetic evolution of SARS-CoV-2 with support from WHO Technical Advisory Group on the Evolution of the SARS-CoV-2 Virus (TAG-VE); (2) Antigenic characterization of previous and emerging SARS-CoV-2 variants using virus neutralization tests with animal antisera or human sera and further analysis of antigenic relationships using antigenic cartography; (3) Immunogenicity data on the breadth of neutralizing antibody responses elicited by currently approved vaccine antigens against circulating variants of SARS-CoV-2 using animal and human sera, including modeling data; (4) Vaccine efficacy evaluations (VE) of currently approved vaccines during the period of circulation of the XBB.1 and JN.1 lines; (5) Preliminary data on the immunogenicity of immune responses after infection with circulating variants of SARS-CoV-2; and (6) Preliminary preclinical and clinical immunogenicity data on the efficacy of vaccine candidates with updated antigens that the vaccine manufacturers confidentially share with TAG-CO-VAC. Further details on the publicly available data reviewed by TAG-CO-VAC can be found in the accompanying data attachment. Unpublished and/or confidential data reviewed by TAG-CO-VAC is not shown.

Summary of available evidence

• SARS-CoV-2 continues to circulate and evolve; there are genetic changes in important regions of the SARS-CoV-2 spike protein.
• As of April 2024, nearly all (>94%) SARS-CoV-2 genetic sequences in publicly available databases are derived from JN.1, and these variants continue to crowd out existing XBB lineage variants (eg, EG.5). This shift indicates a higher fitness of the derived JN.1 variants compared to other circulating SARS-CoV-2 variants in the human population.
• Several JN.1 derived variants (eg, JN.13.1, JN.1.11.1, KP.2) have independently developed changes in the spike protein at epitopes involving amino acid residues 346 and/or 456. Substitutions at these amino acid residues were identified in previous SARS-CoV-2 variants (eg, R346T in BQ.1 and XBB; F456L in EG.5 and HK.3) and are located within epitopes known to be targeted by neutralizing antibodies.
• Given the replacement of lineage XBB variants by JN.1-derived variants, it is likely that, in the near future, circulating SARS-CoV-2 variants will be JN.1-derived.
• In immunologically naïve animal and human sera, XBB.1.5 and JN.1 are antigenically distinct variants of SARS-CoV-2. In naïve animals and humans, post-monovalent XBB.1.5 vaccination sera, with or without recent prior infection, neutralize XBB.1.5 and its derivatives including EG.5, HK.3, HV.1, as well as BA.2.86 and JN.1. However, neutralization titers against JN.1 in published and unpublished studies were typically lower (2-5 fold) than those against the homologous immunizing antigen XBB.1.5. There are further reductions in cross-neutralization of JN.1 variants with F456L and/or R346T substitutions.
• A secondary analysis of published immunogenicity data shows that an additional dose of vaccine with an updated vaccine antigen results in an average increase of 40% in neutralizing antibodies to that variant compared to vaccines with the previous vaccine antigen. Using statistical modeling, the predicted additional vaccine dose efficacy with the updated vaccine antigen may be approximately 23-33% against severe disease compared to the previous vaccine antigen and 11-25% against symptomatic disease.
• In the context of high infection and vaccine-induced immunity in the population, contemporary estimates of vaccine efficacy (VE) are mostly relative (rVE) rather than absolute (comparing vaccinated with unvaccinated individuals) and show additional protection from recent vaccination over and above pre-existing infection and vaccination immunity :
  • Bivalent (index virus and BA.1- or BA.4/5) mRNA vaccines and a beta-based protein vaccine continue to offer protection against severe disease during the circulating period of XBB lineage lineages. Protection against symptomatic disease and infection is lower and disappears more quickly over several months.
  • Monovalent XBB.1.5 vaccines were introduced in some vaccination programs in the last quarter of 2023. Protection against severe disease during the period of circulation of XBB progeny is high during the first three months after vaccination, but protection against symptomatic disease is lower.
  • There are fewer studies evaluating rVE for monovalent XBB.1.5 vaccines during the period of JN.1 progeny circulation. These initial studies show additional protection offered during the first three months after vaccination, but suggest a slight reduction in VE against JN.1, compared to lineage XBB.1 variants, for protection against severe and symptomatic disease. These observations are consistent with the decrease in neutralizing antibody titers observed in preclinical and clinical immunogenicity studies of monovalent XBB.1.5 vaccine sera against JN.1-derived variants.
• Preclinical data confidentially shared with TAG-CO-VAC by the vaccine manufacturers show that immunization of naïve mice, as well as mice previously immunized with SARS-CoV-2 variants, with monovalent JN.1-containing vaccine candidates elicits greater neutralizing antibody responses to JN.1 and its nascent progeny, compared to responses elicited by currently approved vaccines. One human immunogenicity study of a monovalent JN.1-containing vaccine candidate suggests that the JN.1 vaccine antigen is likely to produce more neutralizing antibodies to co-circulating variants of JN.1 (eg, KP.2) than XBB. 1.5 or related vaccine antigen.

TAG-CO-VAC acknowledges several limitations of the available data:

• There are persistent and growing gaps in genetic/genomic surveillance of SARS-CoV-2 globally, including the small number of sequenced samples and limited geographic diversity. TAG-CO-VAC strongly supports the establishment of WHO The coronavirus network (CoViNet) for helping to close this information gap.
• The trajectory of further evolution of SARS-CoV-2 indicates that JN.1 is likely to be the progenitor of SARS-CoV-2 variants in the near future. However, the timing, specific mutations and antigenic characteristics, and the potential impact on public health of emerging (eg KP.2) and future variants remain unknown. TAG-CO-VAC strongly supports the ongoing work of TAG-VE.
• Although neutralizing antibody titers have been shown to be important correlates of protection against SARS-CoV-2 infection and evaluation of vaccine efficacy, there are multiple components of immune protection induced by infection and/or vaccination. Data on immune responses following infection of XBB or JN.1 progeny or vaccination with XBB.1.5 are largely limited to neutralizing antibodies, and data on other aspects of the immune response, including cellular immunity, are limited.
• Data on immunogenicity against currently circulating SARS-CoV-2 variants are not available for all vaccines against COVID-19.
• Evaluations of rVE against recently circulating SARS-CoV-2 variants, including XBB or JN.1 progeny, are limited in terms of number of studies, geographic diversity, evaluated vaccine platforms, evaluated populations, duration of follow-up, and comparative evaluations for monovalent XBB. 1.5 vaccine compared to other formulations delivered during the same time period.

Recommendations for the antigen composition of the vaccine against COVID-19

As of April 2024, almost all circulating SARS-CoV-2 variants reported in publicly available databases are JN.1-derived variants. As viral evolution is expected to continue from JN.1, future vaccine formulations against COVID-19 should aim to induce enhanced neutralizing antibody responses to JN.1 and its progeny. One approach recommended by TAG-CO-VAC is to use a monovalent JN.1 lineage (GenBank: OY817255.1, GISAID: EPI_ISL_18538117, WHO Biohub: 2024-WHO-LS-001) antigens in vaccines.

Continued use of the current monovalent formulation of XBB.1.5 will offer protection given neutralizing antibody responses to early progeny JN.1 and evidence from early rVE studies against JN.1. However, it is expected that the ability of XBB.1.5 vaccination to protect against symptomatic disease may be less robust as the evolution of SARS-CoV-2 continues from JN.1. Other formulations and/or platforms that achieve strong neutralizing antibody responses against currently circulating variants, particularly JN.1 progeny, may also be considered.

In accordance with WHO SAGE policy, vaccination programs should continue to use any of the COVID-19 vaccines on the WHO list for emergency use or prequalified vaccines, and vaccination should not be delayed pending access to updated vaccines. WHO emphasizes the importance of access and equity in the use of all available vaccines against COVID-19.

Further data requirements and considerations

Given the limitations of the evidence on which the above recommendations were derived and the expected continued evolution of the virus, TAG-CO-VAC strongly encourages the generation of data on immune responses and clinical endpoints (ie, VE) on the efficacy of all currently approved COVID-19 Vaccines against emerging SARS-CoV-2 variants and candidate vaccines with updated antigen over time.

As previously stated, TAG-CO-VAC continues to encourage further development of vaccines that can improve protection against infection and reduce transmission of SARS-CoV-2.