Report from the ICMRA/WHO workshop on: Global perspectives on COVID-19 vaccines strain update

Alignment on timing and data requirements

Introduction

There has been continuous and substantial evolution of SARS-CoV-2 since the virus emerged, posing challenges to the ongoing public health response, including that vaccine antigens need updating to continue to provide optimal protection. 

In September 2021, the World Health Organization (WHO) established the Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) to assess the public health implications of emerging SARS-CoV-2 variants on the performance of COVID-19 vaccines and issue timely recommendations to WHO, regulatory authorities and vaccine manufacturers on proposed modifications to vaccine antigen composition. The WHO TAG-CO-VAC continues to meet regularly to evaluate the genetic and antigenic characteristics of circulating SARS-CoV-2 variants, immunity induced by SARS-CoV-2 infection and COVID-19 vaccination, and the performance of authorised COVID-19 vaccines. Based on these assessments, the TAG-CO-VAC provides advice to WHO that is shared with regulatory authorities, and vaccine manufacturers on the implications for COVID-19 vaccine antigen composition [1].

National or regional authorities are responsible for approving the composition and formulation of COVID-19 vaccines used in each country. The International Coalition of Medicine Regulatory Authorities (ICMRA) and WHO, including representatives from TAG-CO-VAC, met on 30 June 2022 [2] and on 8 May 2023 to reach alignment on updating vaccine antigen composition for authorised COVID-19 vaccines. In 2023, ICMRA agreed that the evidence supported the adaptation of the vaccine composition to emerging XBB- descendent lineage Omicron variants [3]. To this end, regulators considered evidence on virus evolution, vaccine effectiveness, and cross-reactivity of authorised vaccines against emerging variants. EMA/ETF published a recommendation for updating vaccine composition on 6 June 2023 [4]. FDA issued a similar recommendation on 15 June 2023 following the meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) [5].

Following assessment of the applications to update the composition of authorised COVID-19 vaccines, EMA recommended authorisation of three XBB.1.5-containing COVID-19 vaccines on 30 August, 14 September and 31 October. FDA approved two XBB.1.5-containing mRNA COVID-19 vaccines on 11 September 2023 and authorised an XBB.1.5-containing protein-based COVID-19 vaccine on  3 October 2023 [6].

There appears to be a periodicity in SARS-CoV-2 circulation, with increases in transmission and hospitalisation during the winter seasons in temperate climates. At the present time however, there is not yet evidence of seasonality in SARS-CoV-2 transmission or COVID-19 burden. As a result, Public health authorities in these temperate regions have generally recommended vaccination ahead of winter months. Some countries also recommend an additional vaccination during the year for at risk groups such as those of advanced age (e.g., above 80 years old).

A workshop was jointly organised by ICMRA and WHO with the overall aim of identifying a structured and aligned process to optimise timely vaccine antigen composition recommendations and regulatory approval for vaccines with an updated composition. Since the start of the pandemic, ICMRA has put global collaboration at the heart of vaccine development. Three updates to vaccine composition have been recommended by WHO TAG-CO-VAC and approved by various regulatory authorities since the initial approval of COVID-19 vaccines in 2020. While COVID-19 vaccines continue to be effective in providing protection against severe disease, the virus continues to evolve, and current vaccines may become less effective over time, potentially leaving individuals under protected.

The objectives of the workshop were:

1. Achieve a common understanding by various stakeholders of the global needs based on reflections from the first 3 years of vaccine use, including i) evidence required for and timing of recommendations from TAG-CO-VAC and regulatory authorities on updated vaccine composition; ii) time required by manufacturers across various vaccine platforms to develop vaccine products with an updated composition, update the manufacturing process and prepare the related regulatory application; iii) regulatory and timing requirements for approval by regulatory agencies.
2. Outline the process and timing for periodic vaccine antigen recommendations for COVID-19 vaccines, when warranted, by the responsible global and regional authorities
3. Agree on regulatory data requirements for manufacturers of authorized/approved vaccines to support a strain change variation to their dossier (quality, non-clinical, clinical) 
4. Consider impact of a global process on regional specificities where relevant (e.g. SARS-CoV-2 variant circulation in different regions of the world).
5. Discuss aspects of communication related to COVID-19 vaccine antigen recommendations.
    

Global perspectives from the first 3 years of COVID-19 vaccine use and antigen composition update

During the first day of the workshop, WHO, regulators, scientists, and industry presented their perspectives and experience in updating COVID-19 vaccine composition, including evidence and timelines required to develop and authorise the updated formulations.

Prof. Anurag Agrawal presented an overview of the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE), a technical advisory group of global experts that monitors and assesses SARS-CoV-2 variants and evaluates their impact on countermeasures, including vaccines, therapeutics and diagnostics, and the effectiveness of public health and social measures. TAG-VE advises WHO as to which variants need further investigation and on the public health risks posed by those variants. SARS-CoV-2 variant risk assessments initially consider growth advantage, followed by evidence as to whether genetic mutations appear to affect transmissibility, immune escape, and/or a change in clinical presentation or disease severity. Variants are classified by WHO as variant under monitoring, variant of interest or variant of concern.

Current variants continue to be derived from Omicron, and are genetically and phenotypically distinct from pre-Omicron variants, although there is increasing genetic diversity within the Omicron variants. The predominant SARS-CoV-2 variant at the current time is JN.1. In its most recent risk assessment of JN.1,  WHO concluded that JN.1 shows greater transmissibility, greater immune escape, but no increase in severity, reduction in vaccine effectiveness against severe disease or increased burden on national public health systems compared to other Omicron sub-lineages [7].

The work of TAG-VE rests on the generation and sharing of genetic and surveillance data from across the globe. However, the generation of data on SARS-CoV-2 surveillance (clinical cases reported, genetic sequencing) has substantially decreased, which makes data interpretation challenging. For this reason, WHO is increasing efforts to sustain surveillance for SARS-CoV-2, including wastewater surveillance and the integration of SARS-CoV-2 into existing respiratory pathogen surveillance systems. WHO has also established a Coronavirus network (CoViNeT [8]) to facilitate global expertise and capacity for early and accurate detection as well as monitoring and genotypic and phenotypic assessment of coronaviruses of public health importance, including SARS-CoV-2.

Florian Krammer from the Icahn School of Medicine at Mount Sinai gave an overview of published data on immune responses to SARS-CoV-2 variants, with a focus on XBB descendant variants and JN.1. Data in mice [9][10] and hamsters [11][12] show that vaccination with an XBB.1.5 monovalent vaccine continues to neutralise recent SARS-CoV-2 variants, including BA.2.86 variant and derivatives, albeit to a lesser extent than XBB.1.5 itself, and that this drop in cross-neutralisation varies based on background vaccination and infection history.  In humans, sera from individuals with XBB.1.5 infection without XBB.1.5 monovalent vaccine neutralised JN.1 but to a lesser extent than sera from individuals who received an XBB.1.5 monovalent vaccine [13]. Other data are also showing that updated vaccines may induce more cross-neutralising antibodies rather than specific antibodies against the new variants [14]. The possibility that the XBB.1.5 spike protein may be more immunogenic than other spike proteins should also be kept in mind [15]. Importantly, recent data suggest that T cell responses against JN.1 may be maintained [16]. In conclusion, immunological profiles are becoming increasingly complex and it is important that animal and human data on immune responses following infection and/or vaccination continue to be generated to inform decisions on vaccine antigen composition.

Daniel Feikin from WHO discussed the use of COVID-19 vaccine effectiveness (VE) studies to support recommendations for updates to COVID-19 vaccine composition. The main challenges are the decreasing number of studies providing VE estimates and the time needed to generate estimates against circulating variants (currently approximately three months after an updated vaccine is introduced). Moreover, a direct comparison of VE between an updated composition and previous formulations may not always be feasible, as an updated vaccine tends to replace previous formulations in vaccination programmes and estimates using a non-contemporaneous comparison are subject to time-varying confounding. Nevertheless, VE studies are useful to monitor how updated vaccines perform in real world settings. To date, they indicate that updated vaccines offer additional protection against symptomatic and severe disease as compared to previous formulations.

Miles Davenport from the Kirby Institute at the University of New South Wales described a mathematical modelling approach to estimate the additional protection provided by an updated COVID-19 composition vaccine. Using immunogenicity data from approximately 30 published studies and an established relationship between neutralising antibody response and protection from COVID-19, boosting with vaccines with an updated composition was found to induce an average 1.4-fold rise in neutralising antibodies as compared to previous vaccine formulations. The data also show that if vaccine antigen composition was not updated at all, the relative benefit of further doses with the same composition would become progressively smaller, resulting in vaccines becoming less effective. Translating the improved booster effect into protection is challenging because it varies with background immunity at population level and the effectiveness of older boosters. However, the predicted additional effectiveness of an updated booster (with 1.4-fold higher neutralising antibody titre) would be about 23-33% against severe disease as compared to the vaccine from the previous season and 11-25% against symptomatic disease.

Kanta Subbarao and David Wentworth – the Chair and Vice-Chair of the WHO TAG-CO-VAC – gave an update of the role of TAG-CO-VAC and its recommendations on the antigen composition of COVID-19 vaccines since its inception[17][18][19]. The objective of updating vaccine composition is to achieve broadly cross-reactive immune responses in the context of continued SARS-CoV-2 evolution, rather than trying to match circulating variants. The ongoing priorities required for TAG-CO-VAC in order to be able to make evidence-informed recommendations on COVID-19 vaccine antigen composition include: assessments of SARS-CoV-2 evolution, including the genetic and antigenic characteristics of earlier and current SARS-CoV-2 variants, and the impact of SARS-CoV-2 evolution on cross-neutralization and cross-protection following vaccination and/or infection; antigenic cartography analysing antigenic relationships of SARS-CoV-2 variants using naïve animal sera and human sera following vaccination and/or infection; evaluation of cellular (T and B cell) immune responses following vaccination and/or infection; animal and/or human data that demonstrate the breadth in immune responses elicited by currently approved vaccines, as well as any vaccine candidates in development, against circulating SARS-CoV-2 variants [20]; and estimates of vaccine effectiveness of currently approved vaccines, or efficacy of vaccine candidates in development.

Decisions as to when to update COVID-19 vaccine composition need to balance the available epidemiological, immunological, and virological data and the timeframes needed by manufacturers to update the composition of authorized vaccines in order to optimize vaccine distribution and uptake. Making earlier decisions may miss the emergence of antigenically important variants, whereas later recommendations, which could improve antigen selection, may delay downstream activities and negatively impact vaccine availability. 

US FDA David Kaslow, EMA-ETF Manuela Mura and Mohit Khera from TGA Australia provided the views of their respective agencies. To advise on antigen composition for their own jurisdictions, all agencies require the same data as mentioned by WHO, as well as timely engagement with vaccine developers, international regulators, and WHO. In 2024, FDA will convene its Vaccines and Related Biological Products Advisory Committee on 16 May with an aim to approve updated vaccines by August. The EMA Emergency Task Force plans to issue their recommendation for the EU in April following recommendations from TAG-CO-VAC. If necessary, depending on the evolving epidemiological situation, WHO, FDA and EMA could issue ad hoc recommendations. TGA presented the process for strain update of COVID-19 vaccines on the basis of the WHO recommendations and on the advice of their Advisory Committee on Vaccines, indicating that accelerated procedures are required to meet planned vaccination campaigns.

Sonali Kochhar, Chair of the WHO SAGE COVID-19 Working group, gave an overview of the WHO SAGE recommendations for COVID-19 vaccination. WHO SAGE supports the use of monovalent XBB.1.5 vaccines when available. However, countries should not delay administration of ancestral or bivalent vaccines if monovalent XBB.1.5 vaccines are not available, since there is a greater benefit in ensuring that persons at high risk of developing severe COVID-19 receive a dose of any available vaccination compared to delayed vaccination [21]. WHO SAGE also emphasizes the ongoing need for equitable access to vaccines, including the updated monovalent XBB.1.5 vaccines, and any future variant-containing vaccines. 

Industry associations IFPMA, Vaccines Europe and DVCMN presented the data from developers on the process and timelines required from data generation to authorisation for any update to vaccine antigen composition. Ongoing challenges highlighted by industry representatives included the worldwide reduction in genomic and epidemiological surveillance data, and the short timelines between vaccine composition recommendation (May/June) and the start of the vaccination campaigns (September/October) in the Northern Hemisphere, especially if pre-approval clinical immunogenicity data is required by regulatory authorities.

During the second day of the workshop, regulators and industry presented their views on regulatory data requirement to support a variation in antigenic composition for authorised/approved vaccines:

Jerry Weir outlined the US FDA process for updating COVID-19 vaccine composition for authorised COVID-19 vaccines and assessment of applications. In terms of regulatory requirements, for vaccines with prior demonstration of efficacy, the data package needed for regulatory review of an update would include comprehensive chemistry, manufacturing and control data to ensure product quality, in addition to preclinical data that supports the effectiveness of the updated vaccine formulation. The need for clinical data prior to authorisation and approval would be based on several criteria, including the experience of the manufacturer, the genetic and antigenic relatedness of the updated component to a previous vaccine, as well as the prior demonstration of efficacy with the specific vaccine platform. Regardless of the vaccine platform, the timelines for production and regulatory approval of an updated formulation are constraining and necessitate some manufacturing activities be performed at risk for a timely vaccine rollout. The manufacturing timelines depend on the vaccine platform, even if some variability among developers exists regardless of the platform.

Elena Grabski from EMA presented more in details the requirements for strain change application from a quality and manufacturing perspective for each vaccine platform currently on the market. For EMA the clinical requirements to support updating vaccine composition are in line with the US FDA. 

Industry associations IFPMA, Vaccines Europe and DVCMN expressed the need for alignment on regulatory data requirements (quality, non-clinical and clinical) and assessment pathways for each update to COVID-19 vaccine composition. CMC data package submission requirements should leverage prior knowledge based on previous composition (e.g. strain analytical and process validations, stability protocol and stability data). Preclinical immunogenicity data continue to be predictive of clinical immunogenicity. However, as hybrid immunity in the general population becomes increasingly complex and diverse, the immune backgrounds in preclinical models that remain relevant needs to be better defined. Clarity is needed, for the same manufacturer’s platform, on how many strain change cycles would be required to remove the requirement for generation of clinical data pre- or post-approval. A predictable and coordinated process for recommendation to update COVID-19 vaccine composition and subsequent regulatory approval is critical to ensure timely availability of updated vaccine. To achieve this, manufacturers propose to harmonise timing of the influenza and COVID-19 vaccines update processes in order to achieve strain selection by mid-May at the latest, approval of variations by July and vaccine deployment from August onwards. Including for mRNA vaccines, a strain selection in May/June would not enable a regulatory review, approval and supply for the fall vaccination campaign, which starts in August/September in many countries. The timeframe expressed by industry to generate pre-clinical data from an update vaccine composition is approximately 2-3 months, with some variability across vaccine platforms. In terms of regulatory and labelling aspects, the following flexibility should be considered: removal of International Non-proprietary Names (INN) requirement; EU common pack rather than multilingual pack requirements; variant agnostic tradename including only the year of the antigen composition; electronic Product Information (e-PI) to expedite and simplify vaccine access (printed leaflets seen as bottleneck to supply). 
 

Process and timing for periodic vaccine antigen recommendations for COVID-19 vaccines 

WHO TAG-CO-VAC will continue to review the evidence to inform COVID-19 vaccine antigen composition updates, when and as needed, and currently plans to meet approximately every 6 months. In 2024 this is planned to occur in April and November. The aim is to reach a predictable recurrence, but with the flexibility to meet ad-hoc if required. The earlier timing for the TAG-CO-VAC recommendation in 2024 as compared to previous years is intended to take into account the current epidemiological situation, the available genetic and antigenic data on SARS-CoV-2 variants and maximise the number of authorised vaccine technologies (mRNA, protein/adjuvanted, inactivated) that are able to produce updated vaccines ahead of vaccination campaigns. Ahead of reaching their recommendations, WHO TAG-CO-VAC will continue to consult with experts, industry and regulators. 

WHO recognizes the balance of updating vaccine composition to enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants but stresses the importance of access to and equity in the use of all available approved COVID-19 vaccines that continue to provide protection against severe disease. 

Regulatory Agencies, in addition to being involved in the WHO consultations with industry as happens for the influenza vaccine strain recommendation process, will continue with specific consultations with industry e.g. in the Northern hemisphere from January/February each year and as needed. Regulators are expected to continue issuing recommendations within their jurisdictions after consultation with WHO and international partners, to ensure consistency for manufacturers to the extent possible. Specific regulatory advice to manufacturers will be issued following the WHO TAG-CO-VAC recommendations. 

Looking at the global picture, a strain recommendation by regulatory authorities in November/December or April/May should allow all authorised vaccine technologies (mRNA, protein/adjuvanted, inactivated) to meet the start of the autumn vaccination campaign in both hemispheres. Ideally recommendations should not be delayed beyond May in the Northern Hemisphere and December in the Southern Hemisphere, unless required by the epidemiological situation. ICMRA will meet as needed to reach a harmonised approach among its members.

ICMRA and WHO agreed on the importance of continuing strong links between agencies and aligned communications. 
 

Data required for vaccine antigen recommendations

ICMRA and WHO agreed that the following data continue to be required to inform COVID-19 vaccine composition recommendations and approvals from TAG-CO-VAC and regulatory authorities: 

• Assessments of SARS-CoV-2 evolution, including the genetic and antigenic characteristics of earlier and current SARS-CoV-2 variants, and the impact of SARS-CoV-2 evolution on antigenicity and immune escape.
• Strengthened epidemiological and virological surveillance to identify if antigenically distinct emerging variants are likely to displace circulating variants in the future.
• Immune responses in animals or humans with the approved antigen composition to indicate levels of cross-reactivity against emerging variants of concern. 
• Estimates of vaccine effectiveness of currently approved vaccines against currently circulating SARS-CoV-2 variants.
• Clinical or non-clinical evaluation of investigational vaccines including updated antigen composition. 

This requires sustained global genetic surveillance and timely data submission, strengthened antigenic assessment of variants, sustained in vitro virological assessment of variants, strengthened assessments of immune responses following infection and vaccination, continued evaluation of the effectiveness of COVID-19 vaccines and further clinical studies, including randomised clinical trials comparing COVID-19 vaccines.
 

Regulatory data requirements for authorised/approved vaccines to support a strain change variation

For already authorised vaccines, clinical trial data with the specific adapted vaccine would not be required prior to approval of the recommended updated composition, provided predictable clinical reactogenicity and immunogenicity with different compositions have been previously demonstrated (use of prior knowledge on a specific vaccine). Based on the experience accumulated so far, it is expected that clinical trial data on one or two strain changes are adequate to demonstrate predictability of performance of the specific product technology, provided no major changes to the manufacturing process or vaccine construct are introduced. Clinical data post-authorization/approval may still be requested since such data is critical for ongoing evaluation of the vaccine composition process.

Prior knowledge and experience with the manufacturing process can expedite the dossier preparation and review and support the data requirements with respect to the characterisation and validation of the updated manufacturing process. Specific considerations are to be expected depending on the type of technology used for manufacturing the vaccine, therefore companies should discuss their CMC/quality package with the respective regulators well in advance of application submission.

In conclusion, and as previously agreed [22], ICMRA confirms that the use of prior knowledge on a specific product can be envisaged for the approval of strain changes for currently authorized or approved COVID-19 vaccines. Spike antigen change procedures should take into consideration all available information and data from studies, and at the present time can be based on quality and non-clinical data. Post-authorization commitments may need to be agreed, e.g., to gather data on vaccine effectiveness against severe outcomes as well as symptomatic disease. Immunogenicity data from clinical trials are to be considered to support future antigen change decisions.

ICMRA regulators did not discuss the antigen composition required to support initial marketing authorization of new vaccines, since this was not an objective of the workshop. It was agreed that initial approval could be based on clinical data of an investigational vaccine, whose composition may not necessarily align with the most recent vaccine antigen recommendations. However, it is expected that the vaccine composition would be updated and approved before vaccine deployment, unless otherwise justified. 
 

Considerations related to regional specificities of virus evolution and circulation

WHO and its advisory groups, including TAG-VE, TAG-CO-VAC and SAGE, will continue to monitor and assess the evolution of SARS-CoV-2 variants and the performance of authorised COVID-19 vaccines. Currently, variant circulation and the epidemiological situation do not necessitate COVID-19 vaccine composition decisions beyond the global level (e.g., for northern and southern hemispheres, or by WHO region). However, regulators in the different regions may consider geographically contextual data and tailor vaccine composition decisions accordingly.

The WHO makes global recommendations for COVID-19 vaccine antigen composition. At the present time there are no apparent differences in SARS-CoV-2 circulation and transmission in the Northern and Southern Hemispheres. The WHO will continue to monitor the epidemiologic and virologic situation and will review the need to update vaccines at least twice a year. 
 

Communication aspects on COVID-19 vaccine antigen recommendations

TAG-CO-VAC will meet at least twice a year to review COVID-19 vaccine antigen composition and TAG-CO-VAC and individual regulators will each issue their own public recommendation. In 2024, the first statement from WHO TAG-CO-VAC on COVID-19 vaccine antigen composition can be expected in late April, followed by recommendations from regulatory authorities. A second decision-making meeting of TAG-CO-VAC will be scheduled for November 2024.  

EMA and FDA among regulatory authorities will issue public statements around their recommendations, ideally during spring in the Northern Hemisphere, to ensure clarity with all stakeholders.
 

Closing remarks

The ICMRA and WHO workshop provided the opportunity for international regulators, authorities, and industry to further discuss perspectives on updating COVID-19 vaccine antigen composition and to propose ways forward. 

The collaboration between ICMRA and WHO has been exceptional throughout the COVID-19 pandemic. There is now the opportunity to put in place a structured process to support and optimise timings around COVID-19 vaccine antigen recommendations. This will include regular meetings with key stakeholders, especially vaccine manufacturers and public health authorities responsible for vaccination recommendations and campaigns. This will contribute to achieve timely production of reagents, regulatory approval and introduction of updated COVID-19 vaccines into vaccination programmes.

[1] Statement on the antigen composition of COVID-19 vaccines (who.int) 
[2] https://www.icmra.info/drupal/covid-19/30june2022 
[3] ICMRA COVID-19 Omicron variant workshop | International Coalition of Medicines Regulatory Authorities (ICMRA) 
[4] EMA and ECDC statement on updating COVID-19 vaccines to target new SARS-CoV-2 virus variants | European Medicines Agency (europa.eu) 
[5] Recommendation for the 2023-2024 Formula of COVID-19 vaccines in the U.S. (fda.gov)
[6] COVID-19 Vaccines for 2023-2024 | FDA
[7] WHO JN.1 Updated Risk Evaluation 9 February 2024
[8] https://www.who.int/groups/who-coronavirus-network
[9] Modjarrad et al., bioRxiv, 2023, https://www.biorxiv.org/content/10.1101/2023.11.17.567633v1.full.pdf  
[10] Patel et al., Scientific Reports, 2023
[11] Coombes et al., bioRxiv, 2024, https://www.biorxiv.org/content/10.1101/2023.10.21.563398v2.full.pdf   
[12] Jworowski et al., Eurosurveillance, 2024 
[13] Wang et al., CHM, 2024 
[14] Liang et al., bioRxiv, 2024, https://www.biorxiv.org/content/10.1101/2024.01.03.574018v1.full.pdf 
Jain et al., bioRxiv, 2024, https://www.biorxiv.org/content/10.1101/2024.02.03.578771v1.full.pdf
[15] Wang et al., CHM, 2024 
[16] Pre-existing SARS-2-specific T cells are predicted to cross-recognize BA.2.86: Cell Host & Microbe 
[17] WHO Interim statement on the composition of current COVID-19 vaccines, 17 June 2022
[18] WHO Statement on the antigen composition of COVID-19 vaccines, 18 May 2023
[19] WHO Statement on the antigen composition of COVID-19 vaccines, 13 December 2023
[20] Key variants considered relevant for demonstrating breadth include the list of Variants of Interest (VOI) and Variants Under Monitoring (VUM): https://www.who.int/activities/tracking-SARS-CoV-2-variants
[21] https://www.who.int/publications/i/item/WHO-2019-nCoV-Vaccines-SAGE-Prioritization-2023.1 
[22] ICMRA COVID-19 Omicron variant workshop | International Coalition of Medicines Regulatory Authorities (ICMRA)