WHO TAG-CO-VAC reviews COVID-19 vaccine effectiveness and antigen composition

The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) continues to closely monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 infection and COVID-19 vaccination, and the performance of COVID-19 vaccines against circulating variants. Based on these evaluations, WHO advises vaccine manufacturers and regulatory authorities on the implications for future updates to COVID-19 vaccine antigen composition. In April 2024, the TAG-CO-VAC recommended the use of a monovalent JN.1 lineage vaccine antigen as one approach to induce enhanced neutralizing antibody responses to JN.1 and its descendent lineages. Several manufacturers (using mRNA and recombinant protein-based vaccine platforms) have updated COVID-19 vaccine antigen composition to monovalent JN.1 lineage formulations (JN.1 or KP.2) and some of these have been approved for use by regulatory authorities. Previous statements from the TAG-CO-VAC can be found on the WHO website.

The TAG-CO-VAC reconvened on 10-12 December 2024 to review the genetic and antigenic evolution of SARS-CoV-2; immune responses to SARS-CoV-2 infection and/or COVID-19 vaccination; the performance of currently approved vaccines against circulating SARS-CoV-2 variants; and the implications for COVID-19 vaccine antigen composition.

Evidence reviewed

The published and unpublished evidence reviewed by the TAG-CO-VAC included: (1) SARS-CoV-2 genetic evolution with additional support from the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE); (2) Antigenic characterization of previous and emerging SARS-CoV-2 variants using virus neutralization tests with animal antisera 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 SARS-CoV-2 variants using animal and human sera; (4) Preliminary immunogenicity data on immune responses following infection with circulating SARS-CoV-2 variants; (5) Available vaccine effectiveness (VE) estimates of currently approved vaccines during periods of circulation of XBB.1 and JN.1 lineages; and (6) Preliminary preclinical and clinical immunogenicity data on the performance of candidate vaccines with updated antigens shared confidentially by vaccine manufacturers with TAG-CO-VAC. 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 reviewed by the TAG-CO-VAC are not shown.

Summary of available evidence

• In 2024, SARS-CoV-2 continues to circulate globally and cause severe disease, post COVID-19 condition and death. The majority of COVID-19 deaths continue to occur in individuals aged 65 years and older and those with coexisting conditions. There are persistent and increasing gaps in the reporting of cases, hospitalizations and deaths, from WHO Member States, making epidemiological trends difficult to infer.
• Currently circulating SARS-CoV-2 variants are all derived from JN.1. The weekly proportion of XEC sequences among all SARS-CoV-2 sequences submitted to GISAID continues to increase, while the weekly proportions of all other Variants of Interest (JN.1) or Variants Under Monitoring (KP.2, KP.3, KP.3.1.1, JN.1.18 and LB.1) are now declining. There are other JN.1-derived variants that are currently in low proportions, but which have mutations that may give them an advantage over XEC: currently LP.8.1, NP.1, LF.7.2 are variants being monitored and/or characterized.
• In published and unpublished data using antisera from naïve animal models, circulating JN.1-derived variants (JN.1, JN.1.16.1, KP.2, KP.2.3, KP.3, KP.3.1.1, LB.1 and XEC) are antigenically closely related.

  • Analysis of naïve mice immunized with mRNA vaccine antigens (KP.3, KP.3.1.1, XEC) showed that JN.1, KP.3.1.1, XEC are antigenically closely related to each other (approximately 1 antigenic unit in cartographic analysis, which corresponds to a two-fold-reduction in neutralization). Antisera to KP.3.1.1 and XEC generate cross-reactive neutralizing antibody titers to each other and to other emerging variants.
  • Antisera from naïve hamsters infected with JN.1 descendent lineages showed that circulating JN.1-derived variants such as KP.3.1.1 are antigenically closely related to JN.1 and to each other (approximately 1 antigenic unit in cartographic analysis). JN.1 antisera showed greater cross-reactivity to KP.2 and KP.3.1.1, as compared to KP.2 antisera.

• In published and unpublished data from humans, vaccination with monovalent JN.1 or KP.2 antigens significantly increased neutralizing antibody titers that cross-reacted with all JN.1 descendent lineages tested.

  • Analysis of pre- and post-vaccination sera from JN.1 or KP.2 immunized individuals demonstrated that vaccination results in strong rises in neutralizing antibody titers against JN.1 and descendent variants, including KP.2, KP.2.3, KP.3, KP.3.1.1 and XEC.
  • Post-monovalent JN.1 or KP.2 vaccination neutralizing antibody titers against KP.3.1.1 and XEC were modestly lower (consistent 2-fold reductions in titers) than those against the homologous JN.1 or KP.2 antigens.
  • There were greater reductions in cross-neutralization of emerging JN.1 lineage variants using post-monovalent XBB.1.5 vaccination sera, as compared to post-monovalent JN.1 or post-monovalent KP.2 vaccination sera.

• In a context of infection- and vaccine-derived immunity in the majority of the population, contemporary vaccine effectiveness (VE) estimates are relative (rVE) rather than absolute (comparing vaccinated to unvaccinated individuals). rVE, sometimes referred to as “up-to-date VE”, demonstrates the added protection of most recent vaccination over and above pre-existing immunity derived from previous infections and/or vaccinations. There are currently studies reporting VE or rVE estimates using monovalent JN.1 lineage (JN.1 or KP.2) vaccines.
• Approved monovalent XBB.1.5 mRNA COVID-19 vaccines continued to provide additional protection against severe disease and death during periods of XBB descendent lineage circulation in the first three months after vaccination; rVE point estimates against symptomatic disease were typically lower. During periods of JN.1 descendent lineage circulation, monovalent XBB.1.5 mRNA vaccines continued to show additional protection in the first three months after vaccination, however, available evidence points towards a reduction in rVE estimates against JN.1-derived variants, as compared to XBB.1 lineage variants, for protection against death, severe disease, symptomatic disease and infection.
• The VE estimates for monovalent XBB.1.5 vaccines against JN.1-derived variants are consistent with reductions in neutralizing antibody titers observed in preclinical and clinical immunogenicity studies of post-monovalent XBB.1.5 vaccination sera against JN.1 descendent variants, as compared to XBB.1 lineage variants.
• Preclinical data shared confidentially with the TAG-CO-VAC by vaccine manufacturers show that immunization of naïve mice, as well as of mice previously immunized with SARS-CoV-2 variants with monovalent JN.1-containing or monovalent KP.2-containing vaccine candidates resulted in good neutralization of JN.1 and descendent variants, including KP.3.1.1, XEC and MC.1. However, neutralizing antibody titers against KP.3.1.1, XEC and MC.1 were approximately 2-fold lower than those against the homologous immunizing antigen. A single preclinical immunogenicity study in mice using an XEC vaccine candidate showed comparable neutralizing antibody titers against JN.1, KP.3.1.1 and XEC as compared to a JN.1 vaccine candidate.
• Clinical data shared confidentially with the TAG-CO-VAC by vaccine manufacturers show that post-monovalent JN.1 sera neutralized JN.1 and its derivatives including KP.3.1.1 and XEC well.

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

• There are persistent and increasing gaps in the reporting of cases, hospitalizations and deaths, from WHO Member States, as well as in genetic/genomic surveillance of SARS-CoV-2 globally, including low numbers of samples sequenced and limited geographic diversity. The TAG-CO-VAC strongly supports the ongoing work of the WHO Coronavirus Network (CoViNet) to address this information gap.

• The timing, specific mutations and antigenic characteristics of emerging and future variants are difficult to predict, and the potential public health impact of these variants remain unknown. There are JN.1-derived variants such as LP.8.1, NP.1 and LF.7.2 that are currently in low proportions, but which have mutations that may give them more immune escape than XEC. These will continue to be monitored and/or characterized. The TAG-CO-VAC strongly supports the ongoing work of the TAG-VE. 
• Although neutralizing antibody titers have been shown to be important correlates of protection from SARS-CoV-2 infection and of estimates of vaccine effectiveness, there are multiple components of immune protection elicited by infection and/or vaccination. Data on the immune responses following JN.1 descendent lineage infection or monovalent JN.1, KP.2 or XBB.1.5 vaccination are largely restricted to neutralizing antibodies. Data and interpretation of other aspects of the immune response, including cellular immunity, are limited. 
• Immunogenicity data against currently circulating SARS-CoV-2 variants are not available for all COVID-19 vaccines. Further, there are very limited data on immune responses following infection in humans with recent SARS-CoV-2 variants (e.g., KP.3.1.1, XEC).
• Estimates of VE against recently circulating SARS-CoV-2 variants, including XBB or JN.1 descendent lineages, are limited in terms of the number and geographic diversity of studies, vaccine platforms evaluated, populations assessed, and duration of follow-up. Furthermore, the referent population for VE estimates varies substantially with respect to prior history of vaccination. There are currently no direct comparative estimates for monovalent JN.1, KP.2 or XBB.1.5 vaccines versus other antigen composition(s) delivered during the same time period. Finally, VE estimates may be confounded by differences in undocumented infection-derived immunity between groups, leading to potential underestimation of VE.

Recommendations for COVID-19 vaccine antigen composition

Given the breadth in immune responses demonstrated by monovalent JN.1 lineage vaccines against circulating variants, the TAG-CO-VAC advises retaining the current COVID-19 vaccine antigen composition, i.e. a monovalent JN.1 lineage variant (NextStrain: 24A, GenBank: PP298019, GISAID: EPI_ISL_18872762) as one approach to induce enhanced neutralizing antibody responses to JN.1 and its descendent variants (e.g., KP.3.1.1 and XEC).

Other approaches that demonstrate broad and robust neutralizing antibody responses against currently circulating JN.1 descendent lineage variants, such as vaccine antigens derived from more recent variants or alternative formulations, could also be considered.

As per the WHO Director General’s standing recommendations for COVID-19, Member States are recommended to continue to offer COVID-19 vaccination based on the recommendations of the WHO SAGE. Vaccination should not be delayed in anticipation of access to vaccines with an updated composition; vaccination programmes can continue to use any available WHO emergency-use listed or prequalified COVID-19 vaccines.

Further data requested

Given the limitations of the evidence upon which the recommendations above are derived and the anticipated continued evolution of the virus, the TAG-CO-VAC strongly encourages generation of the following data (in addition to the types of data outlined in October 2024): 

• • Immune responses and clinical endpoints (i.e. VE and/or comparator rates of infection and severe disease) in varied human populations who receive COVID-19 vaccines with a monovalent JN.1 or KP.2 vaccine antigen composition, across different vaccine platforms, as well as further clinical and laboratory data on the performance of all currently approved COVID-19 vaccines against emerging SARS-CoV-2 variants.
  • Strengthened epidemiological and virological surveillance, as per the Standing Recommendations for COVID-19 in accordance with the International Health Regulations (2005), to determine if emerging variants are antigenically distinct and able to displace circulating variants.
  • Clinical evaluation of relevant new vaccine antigens derived from more recent variants.

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

The TAG-CO-VAC will continue to closely monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 infection and COVID-19 vaccination, and the performance of COVID-19 vaccines against circulating variants. The TAG-CO-VAC will also continue to reconvene every six months to evaluate the implications for COVID-19 vaccine antigen composition. At each meeting, recommendations to either maintain current vaccine composition or to consider updates will be issued.