International regulators have published a report today highlighting their discussions on the effectiveness of current vaccines against the COVID-19 Omicron variant, regulatory requirements for a variant vaccine and considerations on clinical study design. The workshop on the global response to the COVID-19 Omicron variant was organised under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA) and took place on 12 January 2022.

Reviewing data on the impact of Omicron, the participants concluded that current vaccines offer less protection against infection and mild disease caused by this variant. However, vaccination continues to offer considerable protection from hospitalisation and severe COVID-19 with Omicron, especially after a booster dose. It is becoming increasingly clear that a booster dose is needed to extend vaccine protection.

When looking at possible vaccination approaches against Omicron and other virus variants, the meeting participants agreed that the administration of multiple booster doses at short intervals is not a sustainable approach in the longer term. There is a need to develop a long-term strategy on the types of vaccines needed to manage COVID-19 in the future. This is an ongoing global discussion, that sits at the crossroads of science, public policy and public health and will require coordination among public health decision-makers at all levels.

With respect to updated vaccine compositions, global regulators encourage the international scientific community and vaccine developers to look at alternative approaches to monovalent vaccines. In the regulators’ view, companies should also explore the feasibility of developing bivalent or multivalent variant vaccines to determine if they offer advantages to monovalent vaccines.

Meeting participants also stressed that clinical studies should be undertaken to support the use of a new vaccine. These studies should be designed to demonstrate that the immune response, measured as neutralising antibodies, generated by the updated vaccine is superior to that achieved with current vaccines. The ability of the updated vaccines to cross-neutralise other variants of concern would be an additional feature with respect to the breadth of protection provided by the updated vaccine.

The meeting built upon the knowledge and experience gained from previous workshops on COVID-19 vaccine development and virus variants held in 2021, where international regulators emphasised the need for regulatory alignment to expedite and streamline global development and authorisation of new or modified COVID-19 vaccines against emerging coronavirus variants. It brought together delegates representing 24 members and 13 associate members as well as the World Health Organization (WHO).

The meeting was co-chaired by EMA and the US Food and Drug Administration (FDA).

Here is report content:

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 third ICMRA vaccines workshop, following the workshop organised in June 2021 entitled ‘Vaccine development: future steps’. The objective of this workshop was to reach international regulatory alignment on dealing with Omicron variant, on the criteria for the selection of adapted vaccines and fostering a strategic discussion between all public health authorities on the long term needs against SARS-CoV-2. 

How effective are current vaccines against Omicron?

A presentation was given by Dr Singer (Ministry of Health (MoH), Israel) on preliminary data on vaccine effectiveness during the Delta-Omicron transition period in Israel. From the 40% COVID-19 positive cases which were either sequenced or processed via a double PCR strategy, it emerged that the Delta-Omicron transition happened very rapidly within 2 weeks. 

The impact and effectiveness of a third dose of Comirnaty vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel was evaluated by using national surveillance data and applying a negative binomial regression model adjusted for age group, sex, and calendar week. A decrease in vaccine effectiveness (VE) against infection and hospitalization was registered starting around the second week of December 2021 in all age groups. This was attributable to a combination of waning immunity and Omicron breakthrough cases. Israel recently started administering a 4th dose of vaccine to overcome the Omicron wave to subjects 65 years of age and above and with comorbidities. Preliminary MoH data indicated that even when boosting with a third dose there is waning of immunity after 3 months. 

Dr Semete from South African Health Products Regulatory Authority (SAHPRA) presented real-world evidence (RWE) data after 2 doses of Comirnaty vaccine in South Africa. Lower levels of antibodies due to antibody waning were less effective at preventing infection, but they remained effective at reducing disease severity, hospitalization and mortality rate. Regarding Janssen COVID-19 vaccine, while the antibody levels in those vaccinated with the single dose vaccine waned to undetectable level, boosting with a second dose at least 6 months after the first dose clearly improved vaccines efficacy against disease severity and hospitalization. RWE from studies conducted in Canada and UK indicated that despite the drop in VE against Omicron after primary series, an homologous or heterologous booster dose was able to restore high levels of protection in the period shortly after the vaccine administration. Protection from hospitalization is very high after a booster dose, up to 90% according to UK data. Longer follow-up is needed to determine if this level of protection is maintained. More epidemiological data are awaited to confirm if a third dose of the currently approved vaccines offer protection against hospitalization and death in other countries.

Regulatory requirements for variant vaccine: considerations on clinical studies design 

While animal model studies can be considered as important supportive information, at the present time developers should test their candidate vaccines in well-designed clinical trials in order to support approval. Different possible scenarios were presented by Dr Finn from US FDA for the design of clinical studies against variant of concerns for demonstration of effectiveness of modified COVID-19 vaccines. Studies measuring immunogenicity as surrogate endpoint were agreed as being sufficient to demonstrate effectiveness of a modified vaccine. Despite the lack of an established immune correlate of protection, defined as a specific threshold for protection, neutralizing antibodies have shown to be correlated with protection and were deemed the most appropriate immune parameter to measure as primary outcome in the clinical studies. Studies should investigate the adapted vaccine when used for primary vaccination, or as a first or second booster dose after primary vaccination with homologous or heterologous prototype vaccines. In all these different scenarios, the key question to address as primary endpoint of a clinical study is if the antibodies elicited by the modified vaccine neutralize the variant strain better than the prototype vaccine (statistical superiority). Descriptive analyses should be performed on the cross-neutralization of other relevant variants of concern (VOCs). Alternative study designs and analyses may be considered if adequately justified and should be discussed in a timely manner with regulatory agencies.

A change of vaccine composition and manufacturing towards any specific single variant vaccine, e.g. a monovalent Omicron variant vaccine, was considered premature. It was highlighted that more data on the impact of Omicron on the effectiveness of the approved vaccines, as well as a better understanding of the epidemiological evolution of the current Omicron wave are needed to define how urgently an adapted vaccine with a different composition is warranted.

Additional points of discussion were the relevance of data on the breadth, magnitude, and durability of humoral and cell mediated immune responses against circulating VOCs and the performance of the prototype and new vaccines against VOCs. While a monovalent Omicron vaccine would currently represent an obvious candidate to be investigated, other options such as multivalent or bivalent vaccines cannot be ruled out as potential alternatives to be explored to ideally achieve broader cross-protection. The role of the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) group was highlighted in the context of strain selection*.

Closing remarks and next steps

While current vaccines are losing protection against Omicron with respect to infection and mild disease, there is still considerable protection from hospitalisation and severe COVID-19, especially after a booster dose. It is becoming increasingly clear that a booster dose is needed to extend vaccine protection.

Particularly from the perspective of a global strategy, additional boosters of current vaccines administered with short intervals to restore protection over time would not be the preferable approach to protect public health and a longer-term strategy should be defined. 

With respect to updated vaccine composition, other alternatives should be considered besides a monovalent omicron vaccine as it is not yet defined what would be the preferable approach.

In principle, clinical data are needed for approving a new updated vaccine. Clinical studies should demonstrate that the immune response, measured as neutralising antibodies, with the updated vaccine is superior to the immune response achieved with the prototype vaccine against the variant included in the updated vaccine. Cross-neutralisation of other variants of concern would be additional relevant evidence with respect to the breadth of coverage provided by the updated vaccine. These criteria have to be considered as a minimum requirement to support variant vaccine approval.

Global coordination of changes in vaccine composition to cover potential variants of concern will be important. 

Interim Statement on COVID-19 vaccines in the context of the circulation of the Omicron SARS-CoV-2 Variant from the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC)

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