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ICMRA COVID-19 Omicron variant workshop

08 May 2023

Co-chairs: Peter Marks (FDA, US) and Marco Cavaleri (EMA, EU)

Welcome by Emer Cooke, ICMRA chair (EMA)

The ‘COVID-19 Omicron variant’ workshop is the fourth ICMRA vaccines workshop, following the workshop organised in January 2022 entitled ‘COVID-19 Omicron variant’. The objective of this workshop was to reach international regulatory alignment on a potential way forward to adapt authorised and new COVID-19 vaccines to emerging SARS-CoV2 variants. This includes identifying the preferred composition for next updates based on lessons learnt from last year’s strain changes and considerations for simplification of the product information.  

Since the last meeting, WHO has declared that COVID-19 is now an established and ongoing health issue which no longer constitutes a public health emergency of international concern (PHEIC). However, WHO called for countries to consider integrating COVID-19 vaccination into life course vaccination programmes as one of the recommendations from the International Health Regulations Emergency Committee for COVID-19. ICMRA’s input and contributions remain critical to deal with this important public health issue. 

Latest developments on adapted vaccines and options for vaccines updates

A presentation was given by Dr Kanta Subbarao, the Chair of the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) which is convened by WHO to assess the implications of SARS-CoV-2 variants on the performance of COVID-19 vaccines, including any recommendation(s) to update vaccine composition, across all COVID-19 vaccine platforms. The main objective of any update to COVID-19 vaccine antigen composition is to achieve a wider breadth of immunity to ensure protection rather than to target the most recent circulating variant. 

The TAG-CO-VAC convened in March 2023 to review the evidence on the performance of updated COVID-19 vaccines that incorporate descendent lineages of Omicron as a booster dose; and to establish timelines for COVID-19 vaccine composition recommendations in 2023. The group concluded that the virus appears to evolve without jumping back to previous antigenic phenotypes. As such, vaccine-induced immunity may not need to cover variants of concern (VOCs) that are no longer detected in humans. The expert group also reviewed observational epidemiological studies on effectiveness of BA.1 and BA.4/5 containing mRNA vaccines; laboratory-based data on the breadth of cross-reactive immune responses of such vaccines and laboratory-based studies on immune memory responses to evaluate the impact of repeated antigen exposure on vaccine-induced immunity and protection. 

Overall waning of vaccine-induced protection is more significant against infection and mild disease than against severe disease and death and appears to decline around 4 to 6 months from the last vaccination. There is greater and more durable protection against severe disease and death. There is in vitro evidence to show that immune imprinting may occur with repeated exposure to the same antigen, but the clinical impact to date is unclear. Finally, the seasonality of SARS-CoV-2 is still unclear, even if transmission and therefore burden of disease appear to be higher during winter months in temperate locations, as a result of changes in human behaviour. 

The TAG-CO-VAC will meet in May 2023 and every 6 months thereafter (or earlier if needed). At each meeting the genetic and antigenic evolution of SARS-CoV-2 variants, the performance of vaccine products against circulating SARS-CoV-2 variants and the implications for COVID-19 vaccine antigen composition will be assessed. Based on this assessment, recommendations to either maintain current vaccine composition or to consider updates will be issued. In preparation for these meetings, the advisory group will continue to review the available evidence on SARS-CoV-2 variants and their antigenic characteristics, observational studies on effectiveness of COVID-19 vaccines, and immunogenicity data on cross-reactivity of COVID-19 vaccines, including those with an updated antigen composition  against circulating variants, as well as engage with vaccine developers to understand the candidate vaccines in development and timeframes to manufacturing.

Dr. Peter Marks and Dr. Marco Cavaleri gave presentations on the perspective of each regulatory agency concerning the need to update the current vaccine composition and to propose a model for regular data review and vaccine strain change against new VOCs.

U.S. FDA showed evidence that newer VOCs are starting to emerge and slowly increase (XBB.1.16 and XBB.1.9). However, their Spike protein remains generally comparable to XBB.1.5, with additional mutations whose clinical relevance is yet to be fully elucidated. FDA considers beneficial to plan for an annual strain selection around May to allow for vaccine roll out by the Fall in alignment with the influenza vaccination. Data on effectiveness of updated vaccines generated in the Fall campaign will inform the decision for the following season. 

To simplify vaccination in terms of composition, strength, and regimen, FDA considers that individuals from 6YOA until 65YOA could be vaccinated with one dose of vaccine during a periodic vaccination campaign, with a single vaccine composition across vaccine constructs. A 6 years of age cut-off is conservatively based on global epidemiological data indicating that children older than 5 years have largely been exposed one or more time to Spike protein from SARS-CoV-2, either by infection, vaccination, or both. Therefore, individuals at a cut-off below 6YOA may benefit from a primary series consisting of a multidose vaccination regimen which may differ based on the vaccine (2 or 3 doses).

In people aged 65 years and older, an additional dose could be administered 4 months after the periodic single-dose administered to most adults 64YOA and younger.

Considerations should be made for people with compromised immunity, for whom additional doses might be necessary. Because of the wide variety of immunosuppressive conditions, the number of doses and intervals should have enough flexibility to permit health care providers to tailor the vaccine regimen to the individual patient, based on the severity of the condition in line with official local recommendations.

Dr. Marco Cavaleri presented the rate of influenza and COVID-19 hospitalisation in the past years as generated by European Centre for Disease Prevention and Control and by the UK Severe Acute Respiratory Infection Watch network. As previously mentioned, these data show that, even if seasonality for SARS-CoV-2 is not clearly established, most burden of disease is condensed in the winter months. Other human coronaviruses also peak during winter months (January-February), and SARS-CoV-2 is expected to follow a similar pattern in time.  The vast majority of people have been exposed to virus infection or to the vaccine across ages, based on either antibody (>90% seroprevalence based on data generated in Spain *1) or T cell responses (>80% seroprevalence based on data generated in Africa *2).

Data *3 from a large cohort study on vaccine effectiveness indicate that bivalent Wuhan-BA.4/5 vaccines offer an increased protection vs. monovalent Wuhan vaccines against severe infection with omicron BA.4.6, BA.5, BQ.1, and BQ.1.1. Similarly, data from Scandinavian countries from an EMA-founded study *4 show that BA.4/5 bivalent vaccines achieve slightly increased protection as compared to BA.1 bivalent vaccines. This could be due to the fact that the BA.5 Spike is antigenically closer to the Spike of circulating variants, including XBB.1 and BQQ.1. A study in Finland *5 also shows effectiveness of the booster bivalent vaccines against severe disease, wanes over time and as new variants emerge. A small study by Moderna comparing BA.1 bivalent vaccine vs. monovalent original vaccine in terms of efficacy against symptomatic infection indicates that a closer match to circulating strains achieves a higher level of protection.  

T cell epitopes are conserved across variants including XBB descendants, which would explain the protection against severe disease still afforded by the original vaccine, despite the significantly lower humoral immune responses against these most distant variants.
In summary, the evidence presented supports the added value of adapting vaccines to emerging Omicron strains. While waiting for more data, monovalent XBB-containing vaccines could be considered a reasonable choice based on current epidemiology.

Not all the vaccine platforms approved in the EU may be able to provide adapted vaccine this year. In terms of model for future strain changes, EMA would propose to issue recommendations around April/May. These timelines would allow for a timely autumn vaccination campaign for most vaccines. A single dose re-vaccination above 4-5 years of age is also supported by EMA based on current seroepidemiological data. For infants and toddlers, a primary series with the same updated vaccine composition as for re-vaccination could be applied. The route of authorisation used for mRNA vaccines in 2022 could be followed as a model for other vaccines, i.e., the approval of the chosen composition would not require clinical trials data to be generated with the specific adapted vaccine, provided predictable reactogenicity and immunogenicity with different compositions are demonstrated.

*1 Eurosurveillance | Seroprevalence of antibodies against SARS-CoV-2 and risk of COVID-19 in Navarre, Spain, May to July 2022
*2 Anti-inflammatory SARS-CoV-2 T cell immunity in asymptomatic seronegative Kenyan adults | medRxiv
*3 Effectiveness of Bivalent Boosters against Severe Omicron Infection (
*4 Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries (
*5 Bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022 — January 2023 | medRxiv


Outcome of the discussion

A number of points were discussed, and the outcome is hereby summarised:

Vaccines carrying the original strain can still be protective from severe COVID-19 but protection wanes with time and as virus trajectory progressively increase immunological distance. 

  • Real World Evidence (RWE) and immunogenicity data indicate advantages in matching circulating variants and support the added value of adapting vaccines to emerging Omicron strains. Of note, no protection data are available with other constructs such as beta strain vaccines.
  • Pre-clinical immunogenicity data (neutralizing antibody) can provide an indication of how well antibodies to the Spike protein of one strain will cross-neutralize other variant strains of SARS-CoV-2 and thus help to inform strain selection in combination with other data.
  • The XBB family of Omicron subvariants is now dominant and represents the most immunologically distant group of variants in circulation. For this reason, XBB is considered an adequate candidate for vaccine’s composition update. 
  • Monovalent updated vaccines are deemed an appropriate choice to be used as booster, considering the high level of baseline immunity against the ancestral strain. The addition of prior circulating variants or lineages is not likely to provide further benefit.
  • Monovalent updated vaccines could be considered for primary series as well. Since the ancestral strain or previous variants of concern are not in circulation anymore, it is not necessary to keep them in the vaccine formulation going forward.
  • Use of primary series is expected to be confined to young children, e.g., below 4-5 years of age, based on the available sero-epidemiological data. However, it was reflected that these data may change in different parts of the world and so the cut-off could vary accordingly. 
  • There was consensus that a platform approach can be envisaged for the approval of strain changes for currently authorized or approved COVID-19 vaccines. Such approach would only require confirmatory quality and pre-clinical data at time of authorization or approval, provided post-authorization commitments regarding quality, vaccine effectiveness, immunogenicity, and safety data are put in place.
  • It was also reflected that the timing of decision to update vaccine composition has an impact on platform technologies that require more time for manufacturing than mRNA vaccines, and this aspect needs to be considered by regulatory agencies.
  • Flexibility in terms of vaccine strain update can be considered in different regions based on vaccines availability and on demonstration of adequate effectiveness with existing composition.

Closing remarks and next steps 

Current vaccines continue to protect from hospitalisation and severe COVID-19, especially after a booster dose but protection against infection is not durable. Preclinical data show that a vaccine composition that more closely matches currently circulating strains improves immunity to recently emerged XBB descendent lineages.

It is clear that SARS-CoV-2 is continuing to evolve - different omicron descendent lineages that have become dominant over the last 16 months. A COVID-19 vaccine antigen composition that uses a monovalent XBB strains, such as XBB.1.5, would increase the breadth of immunity against XBB descendent lineages. Such monovalent vaccines could be used for both booster and primary vaccinations, the latter envisaged in younger children below 4-5 years of age. Further discussion in anticipation of southern hemisphere vaccination campaigns is warranted. 

Global coordination of changes in vaccine composition going forward is critical to ensure coordination and transparency of decisions. This in turn can facilitate public health decision on vaccination policies and their implementation by health care providers, as well as compliance by the populations in need.