World Health Organization

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The published and unpublished evidence reviewed by the TAG-CO-VAC included: (1) SARS-CoV-2 genetic evolution with support from the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution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.

 

A major landmark study to be published by The Lancet reveals that global immunization efforts have saved an estimated 154 million lives – or the equivalent of 6 lives every minute of every year – over the past 50 years. The vast majority of lives saved – 101 million – were those of infants.

The study, led by the World Health Organization (WHO), shows that immunization is the single greatest contribution of any health intervention to ensuring babies not only see their first birthdays but continue leading healthy lives into adulthood.

Of the vaccines included in the study, the measles vaccination had the most significant impact on reducing infant mortality, accounting for 60% of the lives saved due to immunization. This vaccine will likely remain the top contributor to preventing deaths in the future.

Over the past 50 years, vaccination against 14 diseases (diphtheria, Haemophilus influenzae type B, hepatitis B, Japanese encephalitis, measles, meningitis A, pertussis, invasive pneumococcal disease, polio, rotavirus, rubella, tetanus, tuberculosis, and yellow fever) has directly contributed to reducing infant deaths by 40% globally, and by more than 50% in the African Region.

"Vaccines are among the most powerful inventions in history, making once-feared diseases preventable,” said WHO Director-General, Dr Tedros Adhanom Ghebreyesus. “Thanks to vaccines, smallpox has been eradicated, polio is on the brink, and with the more recent development of vaccines against diseases like malaria and cervical cancer, we are pushing back the frontiers of disease. With continued research, investment and collaboration, we can save millions more lives today and in the next 50 years.”

The study found that for each life saved through immunization, an average of 66 years of full health were gained – with a total of 10.2 billion full health years gained over the five decades. As the result of vaccination against polio more than 20 million people are able to walk today who would otherwise have been paralysed, and the world is on the verge of eradicating polio, once and for all.

These gains in childhood survival highlight the importance of protecting immunization progress in every country of the world and accelerating efforts to reach the 67 million children who missed out on one or more vaccines during the pandemic years.

Monumental efforts to increase access to vaccination over five decades

Released ahead of the 50th anniversary of the Expanded Programme on Immunization (EPI) to take place in May 2024, the study is the most comprehensive analysis of the programme’s global and regional health impact over the past five decades.

Founded in 1974 by the World Health Assembly, EPI's original goal was to vaccinate all children against diphtheria, measles, pertussis, polio, tetanus, tuberculosis, as well as smallpox, the only human disease ever eradicated. Today, the programme, now referred to as the Essential Programme on Immunization, includes universal recommendations to vaccinate against 13 diseases, and context-specific recommendations for another 17 diseases, extending the reach of immunization beyond children, to adolescent and adults.

The study highlights that fewer than 5% of infants globally had access to routine immunization when EPI was launched. Today, 84% of infants are protected with 3 doses of the vaccine against diphtheria, tetanus and pertussis (DTP) – the global marker for immunization coverage.

Nearly 94 million of the estimated 154 million lives saved since 1974, were a result of protection by measles vaccines. Yet, there were still 33 million children who missed a measles vaccine dose in 2022: nearly 22 million missed their first dose and an additional 11 million missed their second dose.

Coverage of 95% or greater with 2 doses of measles-containing vaccine is needed to protect communities from outbreaks. Currently, the global coverage rate of the first dose of measles vaccine is 83% and the second dose is 74%, contributing to a very high number of outbreaks across the world.

To increase immunization coverage, UNICEF, as one of the largest buyers of vaccines in the world, procures more than 2 billion doses every year on behalf of countries and partners for reaching almost half of the world’s children. It also works to distribute vaccines to the last mile, ensuring that even remote and underserved communities have access to immunization services.

“Thanks to vaccinations, more children now survive and thrive past their fifth birthday than at any other point in history,” said UNICEF Executive Director Catherine Russell. “This massive achievement is a credit to the collective efforts of governments, partners, scientists, healthcare workers, civil society, volunteers and parents themselves, all pulling in the same direction of keeping children safe from deadly diseases. We must build on the momentum and ensure that every child, everywhere, has access to life-saving immunizations.”

In 2000, Gavi, the Vaccine Alliance, which includes WHO, UNICEF and the Bill & Melinda Gates Foundation (BMGF) as core founding members, was created to expand the impact of EPI and help the poorest countries in the world increase coverage, benefit from new, life-saving vaccines and expand the breadth of protection against an increasing number of vaccine-preventable diseases. This intensified effort in the most vulnerable parts of the world has helped to save more lives and further promote vaccine equity. Today, Gavi has helped protect a whole generation of children and now provides vaccines against 20 infectious diseases, including the HPV vaccine and vaccines for outbreaks of measles, cholera, yellow fever, Ebola and meningitis.

“Gavi was established to build on the partnership and progress made possible by EPI, intensifying focus on protecting the most vulnerable around the world,” said Dr Sania Nishtar, CEO of Gavi, the Vaccine Alliance. “In a little over two decades we have seen incredible progress – protecting more than a billion children, helping halve childhood mortality in these countries, and providing billions in economic benefits. Vaccines are truly the best investment we can make in ensuring everyone, no matter where they are born, has an equal right to a healthy future: we must ensure these efforts are fully funded to protect the progress made and help countries address current challenges of their immunization programmes.”

Immunization programmes have become the bedrock of primary health services in communities and countries due to their far reach and wide coverage. They provide not only an opportunity for vaccination but also enable other life-saving care to be provided, including nutritional support, maternal tetanus prevention, illness screenings and bed net distribution to protect families from diseases like malaria.

Since the study only covers the health impact of vaccination against 14 diseases, the number of lives saved due to vaccination is a conservative estimate and not a full account of the life-saving impact of vaccines. Societal, economic or educational impacts to health and well-being over the 50 years have also contributed to further reductions in mortality. Today, there are vaccines to protect against more than 30 life-threatening diseases.

While the HPV vaccine, which protects against cervical cancer in adults, was not included in the study, it is expected to prevent a high number of future deaths as countries work towards increasing immunization targets aimed at eliminating cervical cancer by 2030. New vaccine introductions, such as those for malaria, COVID-19, respiratory syncytial virus (RSV) and meningitis, as well as cholera and Ebola vaccines used during outbreaks, will further save lives in the next 50 years.

Saving millions more is “Humanly Possible”

Global immunization programmes have shown what is humanly possible when many stakeholders, including heads of state, regional and global health agencies, scientists, charities, aid agencies, businesses, and communities work together.

Today, WHO, UNICEF, Gavi, and BMGF are unveiling “Humanly Possible”, a joint campaign, marking the annual World Immunization Week, 24-30 April 2024. The worldwide communication campaign calls on world leaders to advocate, support and fund vaccines and the immunization programmes that deliver these lifesaving products – reaffirming their commitment to public health, while celebrating one of humanity’s greatest achievements. The next 50 years of EPI will require not only reaching the children missing out on vaccines, but protecting grandparents from influenza, mothers from tetanus, adolescents from HPV and everyone from TB, and many other infectious diseases.

“It's inspiring to see what vaccines have made possible over the last fifty years, thanks to the tireless efforts of governments, global partners and health workers to make them more accessible to more people,” said Dr Chris Elias, president of Global Development at the Bill & Melinda Gates Foundation. “We cannot let this incredible progress falter. By continuing to invest in immunization, we can ensure that every child – and every person – has the chance to live a healthy and productive life.”

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Notes to editors

For more information on WHO World Immunization Week 2024 campaign, visit World Immunization Week 2024 (who.int) and Humanly Possible campaign, http://itshumanlypossible.org.

Access photos and broll on immunization here.

About the data
WHO led the analysis of the impact of the Expanded Programme on Immunization from 1974 to 2024 with input from researchers from University of Basel, Safinea Ltd., University of Washington, KidRisk Inc., Penn State University, London School of Hygiene & Tropical Medicine, University of Cape Town, Imperial College London, the Vaccine Impact Modelling Consortium, and Institute for Health Metrics and Evaluation. The analysis covers the global and regional health impact of vaccination against 14 diseases: diphtheria, Haemophilus influenzae type B, hepatitis B, Japanese encephalitis, measles, meningitis A, pertussis, invasive pneumococcal disease, polio, rotavirus, rubella, tetanus, tuberculosis, and yellow fever.

About WHO
Dedicated to the health and well-being of all people and guided by science, the World Health Organization leads and champions global efforts to give everyone, everywhere, an equal chance at a safe and healthy life. We are the UN agency for health that connects nations, partners and people on the front lines in 150+ locations – leading the world’s response to health emergencies, preventing disease, addressing the root causes of health issues and expanding access to medicines and health care. Our mission is to promote health, keep the world safe and serve the vulnerable. www.who.int

About UNICEF
UNICEF works in some of the world's toughest places, to reach the world's most disadvantaged children. Across more than 190 countries and territories, we work for every child, everywhere, to build a better world for everyone. For more information about UNICEF and its work, visit: www.unicef.org. Follow UNICEF on Twitter, Facebook, Instagram and YouTube

About Gavi, the Vaccine Alliance
Gavi, the Vaccine Alliance is a public-private partnership that helps vaccinate more than half the world’s children against some of the world’s deadliest diseases. Since its inception in 2000, Gavi has helped to immunize a whole generation – over 1 billion children – and prevented more than 17.3 million future deaths, helping to halve child mortality in 78 lower-income countries. Gavi also plays a key role in improving global health security by supporting health systems as well as funding global stockpiles for Ebola, cholera, meningococcal and yellow fever vaccines. After two decades of progress, Gavi is now focused on protecting the next generation, above all the zero-dose children who have not received even a single vaccine shot. The Vaccine Alliance employs innovative finance and the latest technology – from drones to biometrics – to save lives, prevent outbreaks before they can spread and help countries on the road to self-sufficiency. Learn more at www.gavi.org and connect with us on Facebook and Twitter.

About the Bill & Melinda Gates Foundation
Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people’s health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people—especially those with the fewest resources—have access to the opportunities they need to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Mark Suzman, under the direction of Co-chairs Bill Gates and Melinda French Gates and the board of trustees.