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A new generation of COVID-19 vaccines – the latest developments from preclinical and clinical trials?

In the UK Government strategy ‘Living with COVID’, COVID-19 vaccines represent the first line of defence against SARS-CoV-2. Advances in vaccine technologies allowed manufacturers to develop the first generation of COVID-19 vaccines in record time (see Research from the House of Commons Library and POST on COVID-19 vaccines). Current vaccines are highly effective against hospitalisation and severe disease. However, they present some disadvantages. For instance, all current vaccines are based on the original version of SARS-CoV-2 (first detected in Wuhan in 2019).

Their effectiveness is optimal for that specific virus (that is ‘matched’ to the vaccine) and work less well against symptomatic disease with current variants. Moreover, they are all administered through an injection in the muscle and generate antibodies circulating mainly in the blood rather than in the airways (which are the entry point of SARS-CoV-2). Finally, mRNA-based vaccines (such as the Pfizer/BioNTech and the Moderna vaccine, that together represent most of the vaccines bought by the UK) heavily rely on the cold chain and are harder to distribute in low- and middle-income countries.

New generation COVID-19 vaccines may be able to offer advantages. These include better protection (including against new variants, or for longer time periods) and easier administration, manufacturing and distribution (including increased thermostability). This briefing provides an overview of new generation COVID-19 vaccines. It does not address alternative use of existing vaccines, such as fractional doses or heterologous vaccination strategies. It complements the February 2022 Rapid Response on Addressing COVID-19 in the long term: the role of immunisation.

New vaccines based on modification of current COVID-19 vaccines
Manufacturers have been modifying their already licensed COVID-19 vaccines to adapt them for current variants or to make them easier to administer.

Variant-specific vaccines: latest updates
According to the WHO, the Omicron variant is currently the dominant variant worldwide. The UKHSA vaccine surveillance programme confirms that vaccines currently deployed in the UK (particularly after three doses) are highly effective in protecting against hospitalisation and severe disease with the Omicron variant (both the BA.1 and BA.2 sub-lineages, see COVID-19: Omicron, recent developments, and the likely impact of future variants on the pandemic). However, they are less effective against symptomatic disease. Moreover, protection against symptomatic disease wanes quickly.

Pfizer/BioNTechand Moderna have started clinical-trials for Omicron-specific vaccines. It is uncertain when these vaccines will be available for use. Pfizer/BioNTech started enrolling participants in January 2022, but delays in the data gathering process were reported in February 2022.

Moderna is current trialing the effectiveness of Omicron-specific boosters (including in the UK, supported by the NIHR) and of bivalent boosters combining the original Moderna COVID-19 vaccine with the Omicron-specific one. Preliminary pre-clinical data obtained in animal models (published as pre-print studies, that are not peer-reviewed) show that Omicron-specific boosters developed by the company confer little extra protection in comparison to their standard boosters. Moreover, not peer-reviewed data from mice show that a primary vaccination with Omicron-specific vaccines provides limited protection against the ‘original’ Wuhan SARS-CoV-2 virus and other variants (i.e., Beta and Delta) in comparison to the ‘standard’ Moderna vaccine. The limitations of this study include the fact it is based on animal models and might not translate to humans and that in the future it is unlikely that people are naïve to SARS-CoV2 exposure. Moderna is also developing a single vaccine to target SARS-CoV-2, the influenza virus and the respiratory syncytial virus (RSV), designed to be an annual booster vaccine.

There is consensus among stakeholders that developing vaccines to target specific variants when they are already dominant is not an optimal strategy, as there is a high risk that the new vaccine will be available too late to protect the population.

As discussed during SAGE 88 and SAGE 104, new variants surveillance and characterization before they circulate widely in the population is needed to guide proactive design and selection of ad hoc vaccines. This is referred to as predictive vaccinology. Read POST’s Rapid Response on Addressing COVID-19 in the long-term – the role of immunisation for more information about this and about what can be learnt from influenza surveillance and vaccine selection.

Modifying the administration route of currently available COVID-19 vaccines
Current COVID-19 vaccines are injected in the muscle and generate antibodies that circulate mainly in the blood. While they confer strong protection against hospitalisation and severe disease, their administration route is not optimised to generate antibodies in the airways, which are the entry point of SARS-CoV-2. Mucosal vaccines (either intranasal or oral) have the potential to trigger a robust immune response at SARS-CoV-2 entry site.

According to the WHO’s vaccine tracker, there are 8 intranasal COVID-19 vaccines in clinical trials. Among these, the University of Oxford/AstraZeneca vaccine is currently being trialled as an intranasal formulation in healthy volunteers. Results from Phase 1 trials are expected by the end of March 2022. Pre-clinical trials in animals demonstrated that intranasal administration reduce viral shedding (i.e., the release of virus from an infected individual with the risk that it is transmitted to others).

However, the safety of intranasally administered vaccines could be a potential barrier to acceptability. While intranasal COVID-19 vaccines have been proven safe so far (see this review published by The Lancet for more details on intranasal COVID-19 vaccines, including their safety) previous reported cases of Bell’s palsy (I.e., temporary weakness or lack of movement affecting one side of the face, with most people improving within 9 months) following intranasal vaccination with whole influenza virus might impact their acceptability.

An advantage of intranasal vaccines is that they don’t rely on needles and could potentially facilitate uptake in people with needle phobia (i.e., fear of needles). Other administration routes present similar advantages to intranasal vaccines, including oral vaccines (such as those currently under development by the UK-based biopharma Stabilitech) or skin-patch vaccines (such as the one currently under development by the UK-based Emergex). It is uncertain when these vaccines will be available for use.

New COVID-19 vaccines to ease manufacturing and distribution
Manufacturing and distribution of current COVID-19 vaccines can be challenging. (See Manufacturing COVID-19 vaccines).

To promote the development of vaccines that do not heavily rely on the cold chain, the public-private Coalition for Epidemic Preparedness Innovations (CEPI) recently opened a call to develop thermostable (heat-stable) vaccine technologies to be used for SARS-CoV-2 and other pandemic threats. The UK-based company Stablepharma is currently working on the development of a technology aiming to produce ‘fridge free’ vaccines. It is uncertain when this will be available for use.

Manufacturing can also be eased by modifying vaccine formulation. For instance, adjuvants are vaccine ingredients that enhance the immune system response. They offer the potential to facilitate manufacturing by lowering the doses of active ingredient needed. In the UK, Nuvaxoid, an adjuvanted protein-based vaccine developed by Novavax, was given regulatory approval by the Medicines and Healthcare products Regulatory Agency (MHRA) in February 2022. This vaccine is based on long-established technologies that might be attractive to some of those who are vaccine-hesitant (see COVID-19 vaccine coverage and targeted interventions to improve vaccination uptake for more information on vaccine hesitancy). Another adjuvanted protein-based vaccine developed by Sanofi and GSK is currently seeking regulatory authorisation. The UK Government secured up to 60 million doses of this vaccine candidate.

New COVID-19 vaccines for broader protection
As discussed in a briefing prepared for SAGE 94 by the Vaccine Update Subgroup, future vaccination strategies could benefit from the development of brand new COVID-19 vaccines, designed to offer broader protection (see Addressing COVID-19 in the long term: the role of immunisation).

This could include the development of:

Vaccines able to elicit a strong T-cell response, such CoVac-1, a vaccine developed by the University of Tübingen (Germany) that showed promising results in early clinical trials. Vaccines focused on T-cell response could be more resilient to new variants, as T-cells are able to recognise part of the virus less likely to mutate.

Multivalent vaccines, able to provide protection against different variants at the same time, such as the bivalent booster vaccine currently developed by Moderna (see above).

Universal coronavirus vaccines, able to recognise all coronaviruses or subfamilies of them (for instance, all SARS-CoV-2 variants and viruses causing the common cold). Coronaviruses were responsible for the most recent emerging zoonotic diseases (e.g., SARS, MERS and SARS-CoV-2, see POSTnote 660). Universal coronaviruses vaccines could not only help tackle the current pandemic, but also represent a key aspect of future pandemic preparedness. The public-private Coalition for Epidemic Preparedness Innovations (CEPI) is currently funding several universal coronavirus vaccines under development, including one by the UK-based DIOSynVax.

As stated by the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) on 8 March 2022, while developing these vaccines is desirable, there is uncertainty about the timeframe for their development and production.

Challenges in developing new COVID-19 vaccines
There are several challenges in developing new COVID-19 vaccines, especially with many vaccines already available and deployed. These include:

Maintaining financial incentives to ensure continuous research and development (R&D) from universities and manufacturers;
Running coordinated clinical trials, with flexible trial design to adapt to the pandemic development;
Ensuring efficient and transparent authorisation;
Monitoring vaccine effectiveness in the population. Evaluating effectiveness two years into the pandemic is difficult. The control population (those who didn’t receive any vaccine) is likely to be largely immune because many already had the infection. This has the effect of making vaccines look less effective than they actually are (See also Addressing COVID-19 in the long-term – the role of immunisation).

Other challenges include global supply and deployment. Read more about this topic in the House of Commons Library briefing: Covax: Vaccinating the world against Covid-19 in 2022.