Report from the meeting of the WHO Technical Advisory Group for the composition of the vaccine against COVID-19 (TAG-CO-VAC) held on 16 and 17 March 2023.

In June 2022, TAG-CO-VAC released an interim statement highlighting that virus-based index vaccines continue to provide a high level of protection against severe disease caused by all SARS-CoV-2 Variants of Concern (VOC), including Omicron. However, given the antigenic distance and the uncertainties of the further evolution of the virus, TAG-CO-VAC recognized that the efficacy of vaccines based on the index virus was likely to decrease over time. TAG-CO-VAC therefore advised vaccine manufacturers and regulatory authorities to consider updating the vaccine antigen composition to include Omicron, the most antigenically diverse variant of SARS-CoV-2 to date, for booster use. Multiple vaccine manufacturers have developed COVID-19 vaccines with updated antigenic compositions; these include several bivalent mRNA-based vaccines containing earlier Omicron progeny, in addition to the index virus (ie, index virus + BA.1 or BA.4/5), which have been approved by regulatory authorities for emergency use.

On March 16 and 17, 2023, TAG-CO-VAC reconvened in Muscat, Oman. The purpose of the meeting was twofold: to review the evidence for the effectiveness of updated vaccines against COVID-19 that include Omicron progeny as a booster dose; and set deadlines for recommendations on the composition of the vaccine against COVID-19 in 2023.

The evidence reviewed by TAG-CO-VAC to evaluate the efficacy of the updated COVID-19 vaccines that included Omicron progeny included: (1) published observational epidemiologic studies evaluating the absolute and relative efficacy of BA.1- or BA.4/5-vaccines bivalent mRNA vaccines used as an additional dose against symptomatic and severe disease; (2) laboratory-based data on the magnitude and breadth of cross-reactive immune responses against prior and circulating variants of SARS-CoV-2 elicited by mRNA vaccines containing BA.1 or BA.4/5, compared to the index vaccine-based virus, which they use it as a vaccination; and (3) laboratory studies and observational data on immune memory responses to assess the impact of repeated antigen exposure on vaccine-induced immunity and protection. Further details of the evidence reviewed by TAG-CO-VAC can be found in the attached addition.

Based on the review of the data described above, TAG-CO-VAC concludes:

• Booster doses of virus-based index vaccines continue to provide a high level of protection against severe disease and death caused by all SARS-CoV-2 variants, including modern Omicron descendants.
• Protection against severe disease and symptomatic infections induced by virus-based index vaccines and bivalent mRNA vaccines containing BA.1 or BA.4/5 wanes over time. However, protection against severe disease lasts longer than protection against symptomatic infection.
• Compared with virus-based index vaccines, booster doses of bivalent mRNA vaccines containing BA.1 or BA.4/5 may modestly increase vaccine efficacy against symptomatic disease, while a small number of studies evaluating severe outcomes show similar estimates of vaccine efficacy.
• Both BA.1 and BA.4/5-containing bivalent mRNA vaccines increase the magnitude and elicit a greater breadth of cross-reactive immune responses to SARS-CoV-2 variants when used as a booster dose, compared to the index virus-based vaccine.
• Bivalent mRNA vaccines containing BA.4/5 elicited higher titers of neutralizing antibodies against recent Omicron descendants (BQ.1, XBB.1) compared to bivalent mRNA vaccines containing BA.1, when used as a booster dose.
• It’s there in vitro evidence showing that immune imprinting, also known as antigenic original sin—a phenomenon in which recall of immune memory influences the immune response to a previously encountered antigen—occurs with repeated exposure to the same antigen. However clinical effect of immune imprinting in observational epidemiological studies is not clear to date, due to limited data and the possibility of bias.
• As previously recommended by TAG-CO-VAC in its statement published in June 2022achieving a broader vaccine-induced cross-reactive immune response remains prudent in the context of the continued evolution of SARS-CoV-2.
• Upcoming TAG-CO-VAC meetings will consider the composition of vaccine antigens, including an assessment of whether inclusion of the index virus in future vaccine formulations is warranted. Further recommendations on any updates will be issued by TAG-CO-VAC after its next meeting in May 2023 (see below).
• For any vaccine product with an updated antigen composition, it is imperative to ensure equitable global access.
• TAG-CO-VAC continues to encourage the further development of vaccines that strengthen mucosal immunity as they can improve protection against SARS-CoV-2 infection and transmission.

The role of TAG-CO-VAC is to recommend whether updates to the vaccine composition are needed to continue to safely protect against SARS-CoV-2 variants; while issuing recommendations on vaccination policy Strategic Advisory Group of Immunization Experts (SAGE); the latest SAGE recommendations on COVID-19 disease enhancers can be found here.

TAG-CO-VAC will continue to meet to assess the evidence for updating the antigen composition of the COVID-19 vaccine. To this end, TAG-CO-VAC plans to reconvene twice in 2023: once in May 2023 and again approximately 6 months later. Each meeting will assess the genetic and antigenic evolution of SARS-CoV-2 variants, the efficacy of vaccine products against circulating SARS-CoV-2 variants, and the implications for the antigenic composition of the COVID-19 vaccine. Based on this assessment, recommendations will be issued either to maintain the current vaccine composition or to consider an update. This frequency of evidence review by TAG-CO-VAC is proposed in view of the kinetics of vaccine-derived immunity and the need for continuous monitoring of the development of SARS-CoV-2, and will be adjusted as and when necessary.