Interim statement on booster doses for COVID-19 vaccination

WHO, with support of the Strategic Advisory Group of Experts (SAGE) on Immunization and its COVID-19 Vaccines Working Group, continues to review the emerging evidence on the need for and timing of a booster dose for the currently available COVID-19 vaccines which have received Emergency Use Listing (EUL). This statement reflects the current understanding of vaccine performance and supply.

Definitions:

The following definitions and terminology are used by WHO throughout its policy recommendations on COVID-19 vaccination. This note focuses only on booster doses.

• Booster doses are administered to a vaccinated population that has completed a primary vaccination series (currently one or two doses of EUL COVID-19 vaccine depending on the product) when, with time, the immunity and clinical protection has fallen below a rate deemed sufficient in that population. The objective of a booster dose is to restore vaccine effectiveness from that deemed no longer sufficient. 
  
• Additional doses of a vaccine may be needed as part of an extended primary series for target populations where the immune response rate following the standard primary series is deemed insufficient. The objective of an additional dose in the primary series is to enhance the immune response to establish a sufficient level of effectiveness against disease. In particular, immunocompromised individuals often fail to mount a protective immune response after a standard primary series, but also older adults may respond poorly to a standard primary series with some vaccines. (1)

Global context

The Director-General of WHO has called for a moratorium on booster vaccination for healthy adults until the end of 2021 to counter the persisting and profound inequity in global vaccine access (2).  While many countries are far from reaching the 40% coverage target by the end of 2021, other countries have vaccinated well beyond this threshold, already reaching children and implementing  extensive booster vaccination programmes.  At the time of release of this statement, globally about 17% of COVID-19 vaccine doses, daily, are used for booster or additional dose vaccination.

Vaccine booster dose policy decisions should be based on both evidence of public health benefit and obligations to secure Global Equity in vaccine access as a means to minimize health impacts and transmission, and thereby reduce the risk of variants and prolongation of the pandemic. While vaccine supply is growing, it is not evenly distributed; lower income countries have had far less access, and face unpredictable and irregular supply.  Within countries, equity considerations support improving coverage of the primary vaccination series in high risk populations as the top priority use of vaccine doses. (3)

Public health goals for the administration of booster doses

The WHO roadmap on the prioritization of vaccine use in situations of limited supply (hereafter: the Roadmap), (3) as well as the Strategy to Achieve Global COVID-19 Vaccination by mid-2022(4), define a hierarchy of public health goals in accordance with progressively increasing control of the COVID-19 pandemic. Among those, the primary global goal for the acute phase of the pandemic has been to reduce deaths and severe disease due to COVID-19 and protect health systems. The level of population vaccination coverage needed to achieve this goal may differ between countries.

Subsequent public health goals include the prevention of COVID-19 of any severity and the reduction of transmission, to restore social and economic life, as described in WHO’s Strategy to Achieve Global COVID-19 Vaccination by mid-2022.  This goal and vaccine use case should be pursued only when priority risk groups have full access to vaccine to achieve the primary objective of substantial reduction in severe disease and mortality.  

Evidence of waning protection from primary vaccination series

Emerging data consistently show a decline in vaccine effectiveness (VE) against infection and COVID-19 with time since vaccination with a more significant decline in older adults. This evidence is mostly based on observational studies that may be difficult to interpret due to confounding factors (5).  Current data on the protection against disease requiring hospitalization show an overall robust level of effectiveness for at least six months, although there is some variation in the magnitude of decline across age-groups, target populations, and products (6). The vast majority of current infections are observed in unvaccinated people, and if breakthrough infections occur in vaccinated persons, in most cases they are less severe than those in unvaccinated persons (7).

Based on a recent systematic review and meta-regression analysis facilitated by WHO (8), across the four WHO EUL COVID-19 vaccines with the most data (i.e., BNT162b2, mRNA 1273, Ad26.COV2.S and ChAdOx1-S [recombinant] vaccine), VE against severe COVID-19 decreased by about 8 percent (95% CI 4-15) over a period of 6 months in all age groups.  In adults above 50 years, VE against severe disease decreased by about 10% (95% CI 6 – 15) over the same period.  Vaccine effectiveness against symptomatic disease decreased by 32% (95% CI 11 – 69) for those above 50 years of age.

For some inactivated vaccines, (CoronaVac and COVID-19 vaccine BIBP) WHO has already issued the recommendation for the administration of an additional dose to those aged 60 years or older as part of the primary series to make immunity more robust(9, 10).

The degree of waning of immunity differs between vaccine products and target populations. Circulating viruses, in particular variants of concern (VoC), the extent of prior infection within a community at the time of primary vaccination, the primary vaccination schedule used (i.e., dose interval) and intensity of exposure are all likely to play a role but cannot be systematically assessed from current studies.

Evidence of booster vaccination performance

In several jurisdictions, booster vaccination has been authorized by regulatory authorities and added to the product labels of BNT162b2 and mRNA 1273.  For Ad26.COV2.S and ChAdOx1-S [recombinant] and CoronaVac, COVID-19 vaccine BIBP and BBV152 vaccines, clinical trial data of booster doses are available.  All studies to date show a strong anamnestic immunological response achieving or improving upon the peak antibody levels following the primary immunization series, but with insufficient data and too little follow-up to assess the kinetics and duration of the response.  Both homologous and heterologous booster regimens are immunologically effective. Because no correlate of protection has yet been defined, it is not possible to predict vaccine performance of these heterologous schedules based on the immune response.  Vaccine effectiveness data for a booster dose, which remain confined to a few countries with limited follow-up, show an improvement in protection against infection, milder disease, as well as severe disease and death (11-14) .

Safety and reactogenicity studies are based on small-scale clinical trials and post-licensure data with limited follow-up.  Overall, they show a similar safety profile to that observed after the second dose in the primary series.  Regulatory authorities and advisory bodies have thus assessed a favorable benefit risk ratio of booster vaccination at an individual level.

Factors to be considered when developing a booster vaccination policy

Current situation in countries

At least 107 countries worldwide have already issued recommendations on booster or additional vaccination and more than 99 having started programmatic implementation.  The majority of these countries are classified as high income, or upper middle income. No low-income country has yet introduced a booster vaccination programme.  The most commonly prioritized target populations for booster doses are older adults, health workers and immunocompromised individuals (the last is considered as an additional primary series vaccination dose by WHO).  The degree of primary vaccination coverage in eligible adult population varies, and in several of these countries administering booster doses coverage rates for primary vaccination series are below 30%.

Global equity and supply

In view of the continued inequities in global vaccine access, individual country vaccine booster dose policy decisions need to balance the public health benefits to their population with obligations to support Global Equity in vaccine access.  WHO has re-enforced this message through its call for a global moratorium on booster doses for healthy adults until the end of 2021. 

Of concern are broad-based booster programmes including the booster vaccination of population sub-groups at lower risk of severe disease. While global supply is increasing significantly and should be sufficient for vaccination of the entire adult population globally by the first quarter of   2022, supply will be sufficient to cover extensive use of boosters in adults only later in 2022, should they be broadly needed. During this ramping up phase, hurdles in access and distribution has led to the prevailing inequities that can only be resolved by countries making an effort to assist other countries in need.  

Public health use case and optimization of vaccine impact

In accordance with the Roadmap and WHO’s Strategy to Achieve Global COVID-19 Vaccination by mid-2022, the first priority of a vaccination programme is to reduce mortality and severe disease and to protect health systems. The most important measure to achieve this goal is to maximize coverage among those most likely to become seriously ill and those most likely to become infected.  In order to do this, primary series coverage and selective booster options must be weighed carefully. This priority also contributes to socioeconomic recovery, as the severity of COVID-19 and its potential to overwhelm health systems constitute a primary rationale for public health and social measures that restrict social and economic activity.  To use vaccines first for those at lower risk of severe disease before achieving high primary series coverage for those most likely to become seriously ill will reduce the impact that could be secured with the ongoing limited vaccine supply and runs counter to the National Equity and Equal Respect principles of the Values Framework (15). 

These use case principles are also supported by mathematical modeling on the optimization of public health impact of a limited vaccine supply.  However, as supply increases and vaccination is expanded to lower priority age groups, trade-offs may need to be considered as to prioritizing booster vaccination to high-risk populations over expanding primary immunization coverage to younger populations.  WHO is currently not recommending the general vaccination of children and adolescents as the burden of severe disease in these age groups is low and high coverage has not yet been achieved in all countries among those groups who are at highest risk of severe disease(16). 

Further data needs for developing booster vaccination policies

The decision to recommend a booster dose is complex and requires, beyond clinical and epidemiological data, a consideration of national strategic and programmatic aspects, and importantly an assessment of the prioritization of globally limited vaccine supply. In this context, priority should be given to the prevention of severe disease. Data needs can be grouped into the following categories:

1. Assessing the need for booster doses:  

Epidemiology and burden of disease:  

• Epidemiology of breakthrough cases, by disease severity, age, co-morbidity and risk groups, exposure, type of vaccine and time since vaccination, and in the context of VoCs.

Vaccine-specific data: 

• Efficacy, effectiveness, duration of protection of vaccination in the context of circulating VoCs.
• Supplementary evidence from immunological studies assessing binding and neutralizing antibodies over time, as well as biomarkers of cellular and durable humoral immunity.

2. Assessing the performance of booster doses: 

• Data on efficacy, effectiveness, and duration of protection of homologous and heterologous boosters. 
• Safety and reactogenicity of booster vaccination, including heterologous boosting, needs to be studied at a larger scale.
• Impact of booster vaccination on transmission.

3. Additional considerations include:

• Optimal timing of the booster dose, possibility for dose-sparing for booster doses (e.g. fractional doses), booster needs in previously infected individuals, specification and prioritization of high-risk populations, programmatic feasibility and sustainability, community perception and demand as well as equity considerations.
• Modelling studies to guide strategies to optimize the impact of vaccination.

Conclusions

In the context of ongoing global vaccine supply constraints, broad-based administration of booster doses risks exacerbating inequities in vaccine access by driving up demand and diverting supply while priority populations in some countries, or in subnational settings, have not yet received a primary vaccination series.  The focus of COVID-19 immunization efforts must remain on decreasing death and severe disease. Public health and social measures continue to be an essential component of the COVID-19 prevention strategy.

Introducing booster doses should be firmly evidence-driven and targeted to the population groups in greatest need. Evidence on waning vaccine effectiveness, in particular a decline in protection against severe disease in high-risk populations, may support a decision to introduce booster vaccination. To date, the evidence indicates that protection against severe disease remains high for 6 months after the primary series, but some decrease of the vaccine effectiveness has been observed. Waning of effectiveness against infection is more pronounced.

More data will be needed to understand the potential impact of booster vaccination on the duration of protection against severe disease, but also against mild disease and transmission, and particularly in the context of emerging variants. Over time, as vaccination programmes effectively protect populations from severe disease and death, the protection against milder disease and the reduction of transmission become important additional considerations.

SAGE will deliberate on the evidence for booster doses and the optimization of vaccination programmes during an upcoming Extraordinary SAGE meeting on 7 December 2021.

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References:

1. WHO. Interim recommendations for an extended primary series with an additional vaccine dose for COVID-19 vaccination in immunocompromised persons. 2021 (https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-immunocompromised-persons, accessed 27 November 2021).
2. WHO Director-General's opening remarks at the media briefing on COVID-19 - 8 September 2021. 2021 (https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---8-september-2021 accessed 27 November 2021).
3. WHO. WHO SAGE roadmap for prioritizing uses of COVID-19 vaccines in the context of limited supply. 2021 (https://www.who.int/publications/i/item/who-sage-roadmap-for-prioritizing-uses-of-covid-19-vaccines-in-the-context-of-limited-supply, accessed 27 November 2021).
4. Organization WH. Strategy to Achieve  Global Covid-19 Vaccination   by mid-2022. 2021 (https://cdn.who.int/media/docs/default-source/immunization/covid-19/strategy-to-achieve-global-covid-19-vaccination-by-mid-2022.pdf?sfvrsn=5a68433c_5, accessed 27 November 2021).
5. Krause PR, Fleming TR, Peto R, Longini IM, Figueroa JP, Sterne JAC et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet. 2021. doi: 10.1016/S0140-6736(21)02046-8.
6. Andrews N, Tessier E, Stowe J, Gower C, Kirsebom F, Simmons R et al. Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK. medRxiv. 2021:2021.09.15.21263583. doi: 10.1101/2021.09.15.21263583.
7. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. New England Journal of Medicine. 2021. doi: 10.1056/NEJMoa2109072.
8. Feikin D, Higdon MM, Abu-Raddad LJ, Andrews N, Araos R, Goldberg Y et al. Duration of Effectiveness of Vaccines Against SARS-CoV-2 Infection and COVID-19 Disease: Results of a Systematic Review and Meta-Regression. The Lancet (pre print). 2021. doi: http://dx.doi.org/10.2139/ssrn.3961378.
9. WHO. Interim recommendations for use of the inactivated COVID-19 vaccine BIBP developed by China National Biotec Group (CNBG), Sinopharm: interim guidance. Geneva: World Health Organization; 2021 (https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE-recommendation-COVID-19-vaccine-BIBP accessed 27 November 2021).
10. Organization WH. Interim recommendations for use of the inactivated COVID-19 vaccine, CoronaVac, developed by Sinovac. 2021 (https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-Sinovac-CoronaVac-2021.1 accessed 27 Novemeber 2021).
11. Andrews N, Stowe J, Kirsebom F, Gower C, Ramsay M, Bernal JL. Effectiveness of BNT162b2 (Comirnaty, Pfizer-BioNTech) COVID-19 booster vaccine against covid-19 related symptoms in England: test negative case-control study. medRxiv. 2021:2021.11.15.21266341. doi: 10.1101/2021.11.15.21266341.
12. Barda N, Dagan N, Cohen C, Hernán MA, Lipsitch M, Kohane IS et al. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. The Lancet. 2021. doi: https://doi.org/10.1016/S0140-6736(21)02249-2.
13. Saciuk Y, Kertes J, Shamir Stein N, Ekka Zohar A. Effectiveness of a third dose of BNT162b2 mRNA vaccine. The Journal of Infectious Diseases. 2021. doi: 10.1093/infdis/jiab556.
14. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021. doi: 10.1056/NEJMoa2114255.
15. WHO. WHO SAGE values framework for the allocation and prioritization of COVID-19 vaccination, 14 September 2020. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/who-sage-values-framework-for-the-allocation-and-prioritization-of-covid-19-vaccination, accessed 27 November 2021).
16. Interim statement on COVID-19 vaccination for children and adolescents. 2021 (https://www.who.int/news/item/24-11-2021-interim-statement-on-covid-19-vaccination-for-children-and-adolescents, accessed 27 November 2021).