Statement on the antigen composition of COVID-19 vaccines

Key factors:

• Vaccination stays an necessary public well being countermeasure in opposition to COVID-19. As per the WHO Director General’s standing recommendations for COVID-19, Member States are really helpful to proceed to supply COVID-19 vaccination primarily based on the suggestions of the WHO Strategic Advisory Group of Experts on Immunization (SAGE).
• SARS-CoV-2 continues to flow into and evolve with necessary genetic and antigenic evolution of the spike protein for the reason that starting of the COVID-19 pandemic.
• The goal of an replace to COVID-19 vaccine antigen composition is to reinforce vaccine-induced immune responses to circulating SARS-CoV-2 variants.
• The WHO TAG-CO-VAC advises retaining using a monovalent JN.1 lineage variant because the antigen in future formulations of COVID-19 vaccines.
• In accordance with WHO SAGE coverage, vaccination shouldn’t be delayed in anticipation of entry to vaccines with an up to date composition; vaccination programmes can proceed to make use of any out there WHO emergency-use listed or prequalified COVID-19 vaccines. 

The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) continues to  carefully monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 an infection and COVID-19 vaccination, and the efficiency of COVID-19 vaccines in opposition to circulating variants. Based on these evaluations, WHO advises vaccine producers 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 strategy to induce enhanced neutralizing antibody responses to JN.1 and its descendent lineages.  Several producers (utilizing mRNA and recombinant protein-based vaccine platforms) have up to date COVID-19 vaccine antigen composition to monovalent JN.1 lineage formulations (JN.1 or KP.2) and a few of these have been accredited to be used by regulatory authorities. Previous statements from the TAG-CO-VAC will be discovered on the  WHO website.

The TAG-CO-VAC reconvened on 10-12 December 2024 to evaluate the genetic and antigenic evolution of SARS-CoV-2; immune responses to SARS-CoV-2 an infection and/or COVID-19 vaccination; the efficiency of at the moment accredited vaccines in opposition to circulating SARS-CoV-2 variants; and the implications for COVID-19 vaccine antigen composition.

Evidence reviewed

The printed and unpublished proof reviewed by the TAG-CO-VAC included: (1) SARS-CoV-2 genetic evolution with further assist from the WHO  Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE); (2) Antigenic characterization of earlier and rising SARS-CoV-2 variants utilizing virus neutralization assessments with animal antisera and additional evaluation of antigenic relationships utilizing antigenic cartography; (3) Immunogenicity information on the breadth of neutralizing antibody responses elicited by at the moment accredited vaccine antigens in opposition to circulating SARS-CoV-2 variants utilizing animal and human sera; (4) Preliminary immunogenicity information on immune responses following an infection with circulating SARS-CoV-2 variants; (5) Available vaccine effectiveness (VE) estimates of at the moment accredited vaccines during times of circulation of XBB.1 and JN.1 lineages; and (6) Preliminary preclinical and scientific immunogenicity information on the efficiency of candidate vaccines with up to date antigens shared confidentially by vaccine producers with TAG-CO-VAC. Further particulars on the publicly out there information reviewed by the TAG-CO-VAC will be discovered within the accompanying information annex. Unpublished and/or confidential information reviewed by the TAG-CO-VAC usually are not proven.

Summary of obtainable proof

• In 2024, SARS-CoV-2 continues to flow into globally and trigger extreme illness, submit COVID-19 situation and loss of life. The majority of COVID-19 deaths proceed to happen in people aged 65 years and older and people with coexisting circumstances. There are persistent and growing gaps within the reporting of circumstances, hospitalizations and deaths, from WHO Member States, making epidemiological tendencies troublesome to deduce.
• Currently circulating SARS-CoV-2 variants are all derived from JN.1. The weekly proportion of XEC sequences amongst all SARS-CoV-2 sequences submitted to GISAID continues to extend, whereas the weekly proportions of all different Variants of Interest (JN.1) or Variants Under Monitoring (KP.2, KP.3, KP.3.1.1, JN.1.18 and LB.1) are actually declining. There are different JN.1-derived variants which might be at the moment in low proportions, however which have mutations which will give them a bonus over XEC: at the moment LP.8.1, NP.1, LF.7.2 are variants being monitored and/or characterised.
• In printed and unpublished information utilizing antisera from naïve animal fashions, 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 carefully associated.
  • Analysis of naïve mice immunized with mRNA vaccine antigens (KP.3, KP.3.1.1, XEC) confirmed that JN.1, KP.3.1.1, XEC are antigenically carefully associated to one another (roughly 1 antigenic unit in cartographic evaluation, which corresponds to a two-fold-reduction in neutralization). Antisera to KP.3.1.1 and XEC generate cross-reactive neutralizing antibody titers to one another and to different rising variants.
  • Antisera from naïve hamsters contaminated with JN.1 descendent lineages confirmed that circulating JN.1-derived variants resembling KP.3.1.1 are antigenically carefully associated to JN.1 and to one another (roughly 1 antigenic unit in cartographic evaluation). JN.1 antisera confirmed larger cross-reactivity to KP.2 and KP.3.1.1, as in comparison with KP.2 antisera.
• In printed and unpublished information from people, vaccination with monovalent JN.1 or KP.2 antigens considerably elevated neutralizing antibody titers that cross-reacted with all JN.1 descendent lineages examined.
  • Analysis of pre- and post-vaccination sera from JN.1 or KP.2 immunized people demonstrated that vaccination leads to robust rises in neutralizing antibody titers in opposition to JN.1 and descendent variants, together with KP.2, KP.2.3, KP.3, KP.3.1.1 and XEC.
  • Post-monovalent JN.1 or KP.2 vaccination neutralizing antibody titers in opposition to KP.3.1.1 and XEC have been modestly decrease (constant 2-fold reductions in titers) than these in opposition to the homologous JN.1 or KP.2 antigens.
  • There have been larger reductions in cross-neutralization of rising JN.1 lineage variants utilizing post-monovalent XBB.1.5 vaccination sera, as in comparison with post-monovalent JN.1 or post-monovalent KP.2 vaccination sera.
• In a context of infection- and vaccine-derived immunity within the majority of the inhabitants, modern vaccine effectiveness (VE) estimates are relative (rVE) somewhat than absolute (evaluating vaccinated to unvaccinated people). rVE, typically known as “up-to-date VE”, demonstrates the added safety of most up-to-date vaccination over and above pre-existing immunity derived from earlier infections and/or vaccinations. There are at the moment research reporting VE or rVE estimates utilizing monovalent JN.1 lineage (JN.1 or KP.2) vaccines.  
• Approved monovalent XBB.1.5 mRNA COVID-19 vaccines continued to offer further safety in opposition to extreme illness and loss of life during times of XBB descendent lineage circulation within the first three months after vaccination; rVE level estimates in opposition to symptomatic illness have been sometimes decrease. During durations of JN.1 descendent lineage circulation, monovalent XBB.1.5 mRNA vaccines continued to indicate further safety within the first three months after vaccination, nonetheless, out there proof factors in direction of a discount in rVE estimates in opposition to JN.1-derived variants, as in comparison with XBB.1 lineage variants, for defense in opposition to loss of life, extreme illness, symptomatic illness and an infection.
• The VE estimates for monovalent XBB.1.5 vaccines in opposition to JN.1-derived variants are in line with reductions in neutralizing antibody titers noticed in preclinical and scientific immunogenicity research of post-monovalent XBB.1.5 vaccination sera in opposition to JN.1 descendent variants, as in comparison with XBB.1 lineage variants.
• Preclinical information shared confidentially with the TAG-CO-VAC by vaccine producers present that immunization of naïve mice, in addition to of mice beforehand 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, together with KP.3.1.1, XEC and MC.1. However, neutralizing antibody titers in opposition to KP.3.1.1, XEC and MC.1 have been roughly 2-fold decrease than these in opposition to the homologous immunizing antigen. A single preclinical immunogenicity research in mice utilizing an XEC vaccine candidate confirmed comparable neutralizing antibody titers in opposition to JN.1, KP.3.1.1 and XEC as in comparison with a JN.1 vaccine candidate.
• Clinical information shared confidentially with the TAG-CO-VAC by vaccine producers present that post-monovalent JN.1 sera neutralized JN.1 and its derivatives together with KP.3.1.1 and XEC properly.

The TAG-CO-VAC acknowledges a number of limitations of the out there information: 

• There are persistent and growing gaps within the reporting of circumstances, hospitalizations and deaths, from WHO Member States, in addition to in genetic/genomic surveillance of SARS-CoV-2 globally, together with low numbers of samples sequenced and restricted geographic range. The TAG-CO-VAC strongly helps the continued work of the WHO  Coronavirus Network (CoViNet) to deal with this data hole.

• The timing, particular mutations and antigenic traits of rising and future variants are troublesome to foretell, and the potential public well being affect of those variants stay unknown. There are JN.1-derived variants resembling LP.8.1, NP.1 and LF.7.2 which might be at the moment in low proportions, however which have mutations which will give them extra immune escape than XEC. These will proceed to be monitored and/or characterised. The TAG-CO-VAC strongly helps the continued work of the TAG-VE. 
• Although neutralizing antibody titers have been proven to be necessary correlates of safety from SARS-CoV-2 an infection and of estimates of vaccine effectiveness, there are a number of elements of immune safety elicited by an infection and/or vaccination. Data on the immune responses following JN.1 descendent lineage an infection or monovalent JN.1, KP.2 or XBB.1.5 vaccination are largely restricted to neutralizing antibodies. Data and interpretation of different features of the immune response, together with mobile immunity, are restricted. 
• Immunogenicity information in opposition to at the moment circulating SARS-CoV-2 variants usually are not out there for all COVID-19 vaccines. Further, there are very restricted information on immune responses following an infection in people with latest SARS-CoV-2 variants (e.g., KP.3.1.1, XEC).
• Estimates of VE in opposition to lately circulating SARS-CoV-2 variants, together with XBB or JN.1 descendent lineages, are restricted by way of the quantity and geographic range of research, vaccine platforms evaluated, populations assessed, and length of follow-up. Furthermore, the referent inhabitants for VE estimates varies considerably with respect to prior historical past of vaccination. There are at the moment no direct comparative estimates for monovalent JN.1, KP.2 or XBB.1.5 vaccines versus different antigen composition(s) delivered throughout the identical time interval. Finally, VE estimates could also be confounded by variations in undocumented infection-derived immunity between teams, resulting in potential underestimation of VE.

Recommendations for COVID-19 vaccine antigen composition

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

Other approaches that display broad and sturdy neutralizing antibody responses in opposition to at the moment circulating JN.1 descendent lineage variants, resembling vaccine antigens derived from newer variants or different formulations, is also thought of.

As per the WHO Director General’s  standing recommendations for COVID-19, Member States are really helpful to proceed to supply COVID-19 vaccination primarily based on the suggestions of the WHO SAGE. Vaccination shouldn’t be delayed in anticipation of entry to vaccines with an up to date composition; vaccination programmes can proceed to make use of any out there WHO emergency-use listed or prequalified COVID-19 vaccines.

Further information requested

Given the constraints of the proof upon which the suggestions above are derived and the anticipated continued evolution of the virus, the TAG-CO-VAC strongly encourages era of the next information (along with the types of data outlined in October 2024): 

• Immune responses and scientific endpoints (i.e. VE and/or comparator charges of an infection and extreme illness) in various human populations who obtain COVID-19 vaccines with a monovalent JN.1 or KP.2 vaccine antigen composition, throughout totally different vaccine platforms, in addition to additional scientific and laboratory information on the efficiency of all at the moment accredited COVID-19 vaccines in opposition to rising 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 find out if rising variants are antigenically distinct and capable of displace circulating variants.
• Clinical analysis of related new vaccine antigens derived from newer variants.

As beforehand said, the TAG-CO-VAC continues to encourage the additional growth of vaccines which will enhance safety in opposition to an infection and scale back transmission of SARS-CoV-2.

The TAG-CO-VAC will proceed to carefully monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 an infection and COVID-19 vaccination, and the efficiency of COVID-19 vaccines in opposition to circulating variants. The TAG-CO-VAC may even proceed to reconvene each six months to judge the implications for COVID-19 vaccine antigen composition. At every assembly, suggestions to both preserve present vaccine composition or to contemplate updates can be issued.