Interim statement on decision-making considerations for use of variant updated Covid vaccines

The World Health Organization (WHO) with support of Strategic Advisory Group of Experts (SAGE) on Immunization and its COVID-19 Vaccines Working Group, continues to review the emerging evidence on variant-updated vaccines. This statement reflects the current understanding of variants of concern (VOC) and variant-updated vaccines and highlights the gaps in evidence and potential implications for vaccination strategies.

This statement is not a policy recommendation. A policy recommendation will be issued when sufficient data are available on the properties of variant-updated vaccines compared to those based on the ancestral strain. Initially, human data will likely be available for variant-updated versions of mRNA COVID-19 vaccines and be limited to safety and immunogenicity studies. An interim policy recommendation is likely to be based initially on a characterization of the immune response. Considerations would include the magnitude, duration and breadth of the immune response against a range of VOC, and inferred protection against infection, various other clinical endpoints, and safety. Evidence on vaccine effectiveness (VE) against symptomatic illness and severe disease is expected to become available only when variant-updated vaccines have been introduced into broader use. Policy recommendations for variant-updated vaccines will consider formulations (monovalent or bivalent with the ancestral strain), programmatic issues, evidence or likelihood of improved public health impact, and potential risk mitigation against future variants. WHO anticipates that initial recommendations will be constrained by significant data limitations; therefore, post-approval data on safety and effectiveness will be essential to quantify the performance of variant-updated vaccines, and to refine recommendations.

Background

Currently available COVID-19 vaccines are based on the index virus (also referred to as the ancestral strain); however, there has been continuous and substantial SARS CoV-2 viral evolution, particularly in the spike (S) protein. These genomic changes in the virus have resulted in several VOC that have circulated in waves, with varying degrees of immune evasion, some of which have resulted in lower VE of existing COVID-19 vaccines compared to the initial VE against the index virus. The magnitude of the reduction in VE varies by product, schedule, disease outcome, VOC and time since last dose. From January to June 2022, the dominant SARS-CoV-2 variant globally has been the Omicron variant, with emergence of additional sub-lineages (1). The Omicron variant is the most antigenically distinct variant from the index virus and has exhibited the highest degree of immune evasion to current COVID-19 vaccines, compared to the index virus. Current vaccines continue to perform well in preventing severe disease and death due to Omicron, particularly with the use of a booster dose(s). However, protection against infection and symptomatic illness due to the Omicron variant is lower than other variants and declines rapidly, even after a third (booster) dose. Those at highest risk for severe disease, hospitalization, and death remain older persons, those with comorbidities and immunocompromising conditions, and other vulnerable populations as described in the WHO Prioritization Roadmap (2).

Rationale for updating SARS CoV-2 antigen composition in COVID-19 vaccines

The rationale for developing and implementing variant-updated vaccines is to enhance the magnitude, duration, and breadth of immunity afforded by COVID-19 vaccines to enhance public health impact now and in the future, and to mitigate social and economic risks of infection and disease due to SARS CoV-2. While current COVID-19 vaccines have maintained high protection against severe disease and death across all variants seen to date, the objective of variant- updated vaccines would be to provide first, even greater and more durable protection against severe disease and death, and second, to provide broader protection against future variants that are even more antigenically distant to the index virus. These latter two objectives could prevent spread to vulnerable people and reduce the risk of emergence of new variants. Improved protection against symptomatic illness and even transmission would be an additional desired benefit.

Technical Advisory Group on COVID-19 Vaccine Composition

The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) is a group of independent experts which assesses the public health implications of emerging SARS-CoV-2 VOC on the performance of COVID-19 vaccines in order to issue timely recommendations on potential modifications to vaccine strain composition. In its most recent statement, WHO’s TAG-CO-VAC has highlighted that the use of currently licensed vaccines (i.e. those based on the index virus) with a booster dose confers high levels of protection against severe disease and death for all variants, including Omicron. TAG-CO-VAC also reaffirmed that the continued use of currently licensed vaccines for primary vaccination and as a booster dose is appropriate to achieve the primary goals of COVID-19 vaccination. At the same time, eliciting immunity against as broad a range of S protein variants as possible is desirable to retain and potentially improve protection against future variants. Current evidence shows that repeated exposure to SARS-CoV-2 antigens (either through breakthrough infection following vaccination, vaccination following infection, or with ≥ 3 vaccine doses) improves the magnitude and breadth of the antibody response.

There is great uncertainty as to the timing of emergence, extent of global circulation and antigenic characteristics of future variants, but emergence of new variants seems highly likely based on experience to date. The TAG-CO-VAC has advised that the inclusion of Omicron in the composition of an updated vaccine has the potential to elicit a greater breadth of immune response against Omicron, and potentially enhance protection against infection and milder disease due to emerging variants, while retaining and possibly enhancing protection against severe disease. For these reasons, the potential benefit of Omicron updated vaccines should be studied. The TAG-CO-VAC also advised that immune responses to an Omicron-specific vaccine are likely to differ according to an individual’s COVID-19 primary series vaccination status. As a booster dose, an Omicron-specific monovalent vaccine may elicit greater breadth in the immune response than index virus-based vaccine(s). However, when used for the primary series, an Omicron-specific monovalent vaccine is not likely to confer as broad protection as current index virus-based vaccine and is therefore not advised at the current time.

Use-case scenarios

To complement the TAG-CO-VAC statement, SAGE will consider different use-case scenarios for an Omicron-updated vaccine once such a vaccine has received WHO emergency use listing or emergency use authorization by a stringent regulatory authority and as per its mandate to provide policy recommendations. Use-case scenarios will depend on the vaccine’s characteristics, performance, programmatic requirements, and epidemiological settings. Potential use-case scenarios include bivalent versus monovalent vaccines, and will be guided by WHO’s roadmap on prioritizing uses of COVID-19 vaccines.

Increasing vaccine coverage rates and high exposure to Omicron have led to increasing population-level immunity in many countries. Infection and vaccine use has led to a high degree of hybrid immunity (i.e., population-level immunity from both vaccine- and infection-induced immune responses) (3). However, the resulting degree and duration of protective immunity remains uncertain. Variant-updated vaccines can potentially restore individual and broader population-level protection.

Optimal timing of variant-updated boosters will depend on various factors. For example, surges of COVID-19 over the past two years have been attributed to factors including the relaxation of public health and social measures, emergence of new variants, and insufficient vaccine coverage rates. It will likely continue to be difficult to predict the timing of future surges. If supported by data, rollout of variant-updated booster doses might initially be limited to more vulnerable populations as outlined in the WHO SAGE Roadmap(2).

Other considerations for the introduction of variant-updated vaccines:

Introducing new variant-updated vaccines may add complexity and costs to vaccine programmes. Having multiple products in a vaccine programme, some of which are restricted only for boosters while others are for primary series will create substantial complexity for vaccinators, supply chain planning, documentation of individual vaccination status, safety monitoring, programme performance assessments, communication, and community demand. To date, vaccine uptake tends to decline with every additional COVID-19 vaccine dose that is recommended as part of the schedule. However, variant-updated vaccines with superior and broader immunity revert this trend.

Conclusions

WHO will continue to review the COVID-19 epidemiology, genomic surveillance, phenotypic characteristics, vaccine product development evidence, and vaccine effectiveness data, including with respect to variant-updated vaccines if and when these are introduced. The first human immunogenicity data on the Omicron variant vaccines have been announced in June 2022. WHO will issue policy recommendations for different use-case scenarios for an Omicron-updated vaccine once such a vaccine has received WHO emergency use listing or emergency use authorization by a stringent regulatory authority. Relative benefits and risks, cost-effectiveness and programmatic considerations will all need to be considered.

Current vaccines continue to exhibit strong protection against severe disease and death, and therefore achieving high coverage rates with the primary series and first booster doses in the highest and high priority-use groups in every country remains the priority. As we await data on variant-updated vaccines and assess their relative merit, the performance of existing vaccines can be optimized by using additional doses of current vaccines in priority-use groups (4) and by using heterologous schedules (5) as has previously been recommended by SAGE.

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References:

  1. Organization WH. Tracking SARS-CoV-2 variants. (https://www.who.int/activities/tracking-SARS-CoV-2-variants, accessed
  2. WHO. WHO SAGE roadmap for prioritizing uses of COVID-19 vaccines. (https://www.who.int/publications/i/item/who-sage-roadmap-for-prioritizing-uses-of-covid-19-vaccines-in-the-context-of-limited-supply, accessed 20 January 2022).
  3. Organization WH. Interim statement on hybrid immunity and increasing population seroprevalence rates. 2022 (https://www.who.int/news/item/01-06-2022-interim-statement-on-hybrid-immunity-and-increasing-population-seroprevalence-rates, accessed
  4. WHO. Interim statement on the use of additional booster doses of Emergency Use Listed mRNA vaccines against COVID-19. 2022.
  5. WHO. Interim recommendations for heterologous COVID-19 vaccination schedules. (https://www.who.int/news/item/16-12-2021-interim-recommendations-for-heterologous-covid-19-vaccine-schedules, accessed 21 Dec 2021).

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