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In the eighth meeting of the Working Group on Amendments to the International Health Regulations (WGIHR), which was suspended yesterday until 16 May, State Parties to the IHR took a major step towards agreeing on the package of amendments which will be put forward to the World Health Assembly, which takes place from 27 May–1 June.

The amendments, proposed by IHR State Parties in the wake of the COVID-19 pandemic to strengthen the international community’s ability to detect and respond to pandemic threats, will be further discussed at the resumed eighth meeting on 16-17 May with a view to finalizing an agreed package for submission to the World Health Assembly in May for its consideration and, if agreed, formal adoption.

“The International Health Regulations have been the cornerstone of global health security for decades, but the COVID-19 pandemic showed the need to strengthen them in some areas to make them fit for purpose,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “Countries are grasping this historic opportunity to protect future generations from the impact of epidemics and pandemics, with a commitment to equity and solidarity.”

This eighth meeting of the Working Group on Amendments to the IHR (WGIHR) started on 22 April and suspended today. Whilst the process is being held alongside negotiations of the world’s first pandemic agreement to strengthen global collaboration among governments to prepare for, prevent and respond to pandemics, it was proposed in WGIHR8 that two separate Resolutions on the two processes be submitted to the World Health Assembly in May. Negotiations resume on the pandemic agreement on 29 April and continue until 10 May.

During the eighth meeting of the WGIHR, substantial progress on finalizing the package of amendments was made as State Parties reached agreement in critical areas.

WGIHR Co-Chair Dr Ashley Bloomfield said: “The work to bolster our global defenses against public health emergencies and risks, through agreeing a stronger set of International Health Regulations, reflects both the risks our highly interconnected world faces today, and the recognition and readiness of countries to ensure their citizens are better protected.”

Fellow WGIHR Co-Chair, Dr Abdullah Assiri, said the proposed amendments to the IHR are readily implementable and recognize the importance of equity in ensuring effective global response.

“The COVID-19 pandemic showed the world that viruses of pandemic potential do not respect national borders,” Dr Assiri said. “Amending the International Health Regulations reflects the critical need to bolster our collective defenses against current and future public health risks so people’s health, societies and economies can be better protected, all whilst firmly respecting and adhering to the principle of national sovereignty.”

The eighth meeting of the WGHIR will resume in a two-day final session 16-17 May to continue and conclude the work of the Working Group according to its mandate from the Health Assembly

The IHR have 196 State Parties, comprising all 194 WHO Member States plus Liechtenstein and the Holy See. These Parties have led the process to amend the IHR. The Regulations have been negotiated under Article 21 of the WHO Constitution. Any amendment will come into force for all States Parties, after a set period, except for those that notify the WHO Director-General of a rejection or reservation.

Key points

• SARS-CoV-2 continues to circulate and evolve with important genetic and antigenic evolution of the spike protein.
• The objective of an update to COVID-19 vaccine antigen composition is to enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants.
• As the virus is expected to continue to evolve from JN.1, the TAG-CO-VAC advises the use of a monovalent JN.1 lineage as the antigen in future formulations of COVID-19 vaccines.
• In accordance with WHO SAGE policy, vaccination programmes should continue to use any of the WHO emergency-use listed or prequalified COVID-19 vaccines and vaccination should not be delayed in anticipation of access to vaccines with an updated composition.

The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) meets regularly to assess the impact of SARS-CoV-2 evolution on the performance of approved COVID-19 vaccines. This includes meeting in person approximately every six months to determine the implications of SARS-CoV-2 evolution on COVID-19 vaccine antigen composition and to advise WHO on whether changes are needed to the antigen composition of future COVID-19 vaccines. The twice-yearly evidence review by the TAG-CO-VAC is based on the need for continued monitoring of the evolution of SARS-CoV-2 and the kinetics and protection of vaccine-derived immunity.

In May 2023, the TAG-CO-VAC recommended the use of a monovalent XBB.1 descendent lineage, such as XBB.1.5, as the vaccine antigen. In December 2023, the TAG-CO-VAC advised retaining the use of a monovalent XBB.1 descendent lineage, such as XBB.1.5, as the vaccine antigen. Several manufacturers (using mRNA, protein-based and viral vector vaccine platforms) have developed COVID-19 vaccines with a monovalent XBB.1.5 formulation which have been approved for use by regulatory authorities and introduced into COVID-19 vaccination programmes in some countries. Previous statements from the TAG-CO-VAC can be found on the WHO website.

The TAG-CO-VAC reconvened on 15-16 April 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 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 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 SARS-CoV-2 variants using animal and human sera, including modelling data; (4) Vaccine effectiveness estimates (VE) of currently approved vaccines during periods of circulation of XBB.1 and JN.1 lineages; (5) Preliminary immunogenicity data on immune responses following infection with circulating SARS-CoV-2 variants; 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

• SARS-CoV-2 continues to circulate and evolve; there are genetic changes in important regions of the spike protein of SARS-CoV-2.
• 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 displace existing XBB lineage variants (e.g. EG.5). This displacement indicates greater fitness of JN.1 derived variants as compared to other circulating SARS-CoV-2 variants in the human population.
• Several JN.1 derived variants (e.g. JN.13.1, JN.1.11.1, KP.2) have independently evolved changes in the spike protein at epitopes involving amino acid residues 346 and/or 456. Substitutions at these amino acid residues have been identified in previous SARS-CoV-2 variants (e.g. R346T in BQ.1 and XBB; F456L in EG.5 and HK.3) and are within epitopes known to be targeted by neutralizing antibodies.
• Given the displacement of XBB lineage variants by JN.1 derived variants, it is likely that, in the near-term, circulating SARS-CoV-2 variants will be derived from JN.1.
• In immunologically naïve animal and human sera, XBB.1.5 and JN.1 are antigenically distinct SARS-CoV-2 variants. In non-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 titres against JN.1 in published and unpublished studies were typically lower (2-5-fold) than those against the homologous XBB.1.5 immunizing antigen. There are further reductions in cross neutralization of JN.1 variants with F456L and/or R346T substitutions.
• Secondary analysis of published immunogenicity data demonstrates that an additional vaccine dose with an updated vaccine antigen results in an average 40% increase in neutralizing antibodies to that variant as compared to vaccines with a previous vaccine antigen. Using statistical modeling, the predicted additional effectiveness of a vaccine dose with an updated vaccine antigen may be approximately 23-33% against severe disease as compared to a previous vaccine antigen and 11-25% against symptomatic disease.
• In a context of high infection- and vaccine-derived immunity in the population, contemporary vaccine effectiveness (VE) estimates are mostly relative (rVE), rather than absolute (comparing vaccinated to unvaccinated individuals), and demonstrate the added protection of recent vaccination over and above pre-existing infection- and vaccine-derived 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 periods of XBB descendent lineage circulation. Protection against symptomatic disease and infection is lower and wanes more rapidly over several months.
  • Monovalent XBB.1.5 vaccines were introduced into some vaccination programmes in the last quarter of 2023. Protection against severe disease during periods of XBB descendent lineage circulation is high during the first three months after vaccination, but protection against symptomatic disease is lower.
  • There are fewer studies estimating rVE for the monovalent XBB.1.5 vaccines during periods of JN.1 descendent lineage circulation. These initial studies show some additional protection offered during the first three months after vaccination, but point towards a slight reduction in VE against JN.1, as compared to XBB.1 lineage variants, for protection against severe and symptomatic disease. These observations are consistent with reductions in neutralizing antibody titres observed in preclinical and clinical immunogenicity studies of monovalent XBB.1.5 vaccinee sera against JN.1 derived variants.
• Preclinical data shared confidentially with the TAG-CO-VAC by 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 higher neutralizing antibody responses to JN.1 and its emerging descendent variants, as compared to responses elicited by currently approved vaccines. A single immunogenicity study in humans of a monovalent JN.1-containing vaccine candidate suggests that a JN.1 vaccine antigen is likely to produce higher neutralising antibodies to co-circulating JN.1 variants (e.g., KP.2) than an XBB.1.5 or related vaccine antigen.

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

• There are persistent and increasing gaps 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 establishment of the WHO Coronavirus Network (CoViNet) to help address this information gap.
• The trajectory of further SARS-CoV-2 evolution indicates that JN.1 will likely be the progenitor of SARS-CoV-2 variants, in the near term. However, the timing, specific mutations and antigenic characteristics, and the potential public health impact of newly emerged (e.g. KP.2) and future variants remain unknown. The TAG-CO-VAC strongly supports the ongoing work of the TAG-VE.
• Although neutralizing antibody titres 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 XBB or JN.1 descendent lineage infection or XBB.1.5 vaccination are largely restricted to neutralizing antibodies and data on 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.
• Estimates of rVE against recently circulating SARS-CoV-2 variants, including XBB or JN.1 descendent lineages, are limited in terms of the number of studies, geographic diversity, vaccine platforms evaluated, populations assessed, duration of follow-up and comparative estimates for monovalent XBB.1.5 vaccines versus other formulations delivered during the same time period.

Recommendations for COVID-19 vaccine antigen composition

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

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

In accordance with WHO SAGE policy, vaccination programmes should continue to use any of the WHO emergency-use listed or prequalified COVID-19 vaccines and vaccination should not be delayed in anticipation of access to vaccines with an updated composition. WHO stresses the importance of access to and equity in the use of all available COVID-19 vaccines.

Further data requirements and considerations

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 data on immune responses and clinical endpoints (i.e. VE) on the performance of all currently approved COVID-19 vaccines against emerging SARS-CoV-2 variants, and candidate vaccines with an updated antigen over time.

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. 

WHO classifies antibiotics as per AWaRe (Access, Watch, Reserve) classification, according to the risk of AMR. Concerningly, the study found that ‘Watch’ antibiotics with higher resistance potential were most frequently prescribed globally.

The event is taking place on 26-27 April 2024 at the Institut Pasteur and is supported by prominent athletes advocating on the cause ahead of the Paris Paralympics.

WHO welcomed Mr Javier Padilla Bernáldez, Spain’s Secretary of State for Health and his delegation on 23 and 24 April 2024 to discuss joint global health priorities. Amongst others, Spain's focus is on universal health coverage and health systems strengthening; pandemic response and emergency medical teams; organ and tissue transplantation; malaria and other tropical diseases; and polio.

During the visit, participants focused on plans and on-going work across a number of areas, including WHO’s Transplantation Program to increase availability; ethical access and oversight of transplantation of human cells; tissues and organs. They also discussed social determinants of health; tobacco and alcohol control; primary health care; access to medicines; universal health coverage; ensuring healthy lives at all ages; nutrition and food safety; health workforce; and emergencies.

Mr Javier Padilla was accompanied by Ms Paola Cannata Molero, Director of the Cabinet of the Secretary of State for Health, Mr Jacobo Fernández Álvarez, Technical Secretary General, Mr Héctor Tejero Franco, Advisor in the Cabinet of the Minister of Health and Responsible for Health and Climate Change, and Mr Roberto Carro Vázquez, Senior Technician of the Office of the Secretary of State for Health. The delegation also had representatives of Spain’s Permanent Mission to the United Nations Office and Other International Organizations in Geneva, including H.E. Ambassador Ms A. Díaz-Rato Revuelta, H.E. Ambassador Ms Clara Cabrera Brasero, and Counsellor Ms María del Carmen Martínez de la Peña.

The Spanish delegation met with Dr Ailan Li, Assistant Director General (ADG) for Universal Health Coverage, Healthier Populations, Dr Catharina Boehme, ADG for External Relations and Governance, Dr Yukiko Nakatani, ADG for Access to Medicines and Health products and ADG for Antimicrobial Resistance ad interim, Dr Michael Ryan, Deputy Director-General and Executive Director for WHO Health Health Emergencies Programme.

Left to right: Dr Maria Neira, Director, Environment, Climate Change and Health, H.E. Ambassador Aurora Díaz-Rato Revuelta, Dr Javier Padilla Bernáldez, Secretary of State for Health, Michael Ryan, Deputy Director-General and Executive Director, WHO Health Emergencies Programme. Credit: WHO/Chris Black

WHO’s Management and their teams thanked Spain for their financial and technical support over the years. Spain’s support was instrumental in the last biennium in improving access to quality essential health services and medicines; addressing climate change and healthier environments; and strengthening country capacity in both data and innovation. Spain continues to be a champion of the Global Polio Eradication Initiative.

Spain also contributes to WHO’s work in tackling malaria and neglected and other tropical diseases, and has helped the Organization strengthen countries’ preparedness, readiness, prevention and response for health emergencies, epidemics and pandemics. Spain’s contribution to WHO’s Health Emergency Appeal has helped to protect health in humanitarian emergencies to break the cycles of poverty.

As a world leader in the field of organ and tissue transplantation, Spain plays a key role in WHO’s efforts through its Ministry of Health to improve the safety, quality, efficacy and access to transplants. WHO appreciates and acknowledges Spain as a partner who is not only leading and sharing expertise in support of countries’ development of sustainable, self-sufficient organ transplant systems, but also more generally, a key partner to WHO in health for all.