Better late than never? What developers of SARS-CoV-2 vaccines in early-to -late-stage development should consider

by Michael Pfleiderer, Ilona Baraniak and Ciaran Greene

Surely, the year 2020 will be remembered by history as a year of pandemic and emergency state, during which our normal routines were disrupted, the health systems and emergency responses had to be urgently and radically reshaped on a local and global level to address public health needs. On the other hand, we have witnessed an unprecedented speed and flexibility in the development of vaccines, anti-viral therapeutics, and novel technologies.

These unprecedented efforts to develop preventive and therapeutic measures showed tremendous success. Just over a year from the onset of the pandemic we have vaccines and therapeutics licensed in almost all parts of the world. In the EU, four vaccines have already received a Conditional Marketing Approval (CMA) from EMA and vaccination programs have been implemented in all the 27 EU Member States and beyond. Despite this, increasing transmission of COVID-19 is currently observed in most countries in the WHO European Region and other parts of the world. This is caused by the emergence of more infectious virus variants, slow vaccination roll-out accompanied by shortages of supplies and problems with manufacture.

As evidenced recently, SARS-CoV-2 acquires mutations, resulting in the emergence of more infectious and possibly more pathogenic variants of the virus. Emergence of the current variants adapting to the human host and variants emerging from natural and vaccine induced immunity may exhibit a certain level of resistance to naturally or vaccine acquired immunity. Of course, such an “immunological escape” of the VOCs might impede the effectiveness of currently used vaccines, forcing manufacturers to periodically exchange the vaccine antigens to better address the emerging variants.

On the other hand, we should consider whether we should solely rely only on these already approved vaccines, or further develop also those that are currently in the pipeline. Although the development of many vaccine platforms comes relatively late, it is important to note that those may still have a great potential, as we are still far from reaching the end of the current pandemic. Technical problems connected with the production of billions of doses, stability issues, and ethical issues connected with the availably of these vaccines in the poorest countries are just some of the imminent challenges we face. Apart from these logistical and supply issues, one of the most important threats to successful global vaccination is, of course, the abovementioned emerging new virus variants.

Therefore, unsurprisingly, some opinion leaders already stated that “in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants” [1]. As such, a broad array of vaccines based on different technologies is very important as it will allow to select those that can be most effective in specific phases of the pandemic and in different parts of the world.

As such, we should continue evaluating the usefulness of novel technologies and the feasibility of licensure in the EU and other geographic areas. Also, it is important to emphasise that given the current urgent need for prophylactic vaccines, EMA has adopted a very flexible approach, allowing unprecedented time-saving solutions as long as the safety of the vaccine recipients remains uncompromised. The regulatory assessment of COVID-19 vaccines is greatly modified as opposed to the conventional approach. This offers a possibility of using vaccines that are still under development during the current pandemic as supporting tools to the already existing vaccination programs.

How to plan a phase III study?

Of course, coming late means that the development program must be modified according to current circumstances and requirements. As vaccines are already available, execution of large Phase III efficacy trials with placebo are no longer considered necessary, moreover such trials may be viewed as unethical by some regulatory authorities. Furthermore, recruitment of unvaccinated candidates for clinical trials is becoming more and more difficult.

With the practical and ethical challenges of conducting placebo-controlled efficacy trials, many second generation COVID-19 vaccine developers now consider whether vaccine efficacy can be inferred, exploring alternative approaches using an immune correlate of protection (CoP) or immune bridging studies. An immune CoP is an immunological response that correlates with vaccine-induced protection against a certain infectious disease and can be considered predictive of clinical efficacy. However, as there is currently no established CoP for COVID-19, vaccine developers are turning to performing immune bridging, or non-inferiority Phase III clinical trials.

Non-inferiority designs are used to demonstrate a non-inferior response of a candidate vaccine against a licensed comparator vaccine for estimating vaccine efficacy against a specific disease, and bridging established vaccine efficacy to extended populations and regions [2]. Several recent studies support the implementation of a Phase III non-inferior design for second generation COVID-19 vaccine developers, suggesting a correlation between vaccine/convalescent ratio for both binding and neutralizing antibodies and vaccine efficacy [3, 4]. Within these studies, evaluation across different vaccine platforms among several approved COVID-19 vaccines also shows a high correlation between neutralizing and binding antibody titres with vaccine efficacy, despite geographically diverse study populations which were subject to different circulating variants, endpoints, and assays. These results strongly support the use of post immunisation antibody levels as the basis for a CoP.

Immune bridging studies can now be planned in accordance with FDA, EMA and ACCESS consortium (Australia, Canada, Singapore, Switzerland, and UK) guidance’s among others [5-7]. These approaches outline the considerations for planning non-inferiority trials, showing a high alignment on key features. These guidelines are however tailored towards adapting a variant strain to a licensed vaccine, on the basis the adapted vaccine should use the same manufacturing process and sites as the approved “prototype” vaccine. Therefore, it is primarily very important for second generation COVID-19 vaccine developers to select a suitable licensed comparator vaccine for initial Phase III immune bridging trials, while simultaneously planning the future transition to an adapted vaccine with a variant antigen. 

Which antigens should be used?

With the emergence of several SARS-CoV-2 VOCs worldwide, considerations for the design of Phase III clinical trials and the choice of the antigen becomes critical to facilitate a smooth and streamlined pathway to licensure. With the recent reporting of the B.1.617 variant strain from India, referred to as the “double mutant” variant, the quick adaption of vaccines is more important than ever. This B.1.617 strain adds to the growing list of reported SARS-CoV-2 variants worldwide including: B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil) [8-10].

The increasing number of recent variant strains also forces COVID-19 vaccine manufacturers to assess which antigen they should base their development program on. With increasing cases of reported variant strains worldwide, how can late developers plan for the future? Should they keep focus on the development of vaccines with reference to the original SARS-CoV-2 Wuhan strain?

In short, developers should still incorporate the antigen corresponding to the Wuhan strain, as all current licensed vaccines were authorised on the basis of demonstrating efficacy against this strain. In order to perform a Phase III immune bridging study, non-inferior efficacy or immunogenicity with a candidate vaccine must be demonstrated against a licensed comparator vaccine.

However, as outlined by CEPI and the WHO as part of a recent COVAX workshop in March [11], vaccines approved with demonstrated clinical vaccine efficacy against the original SARS-CoV-2 virus (D164G), may not be efficient enough against currently circulating SARS-CoV-2 VOCs. With this in mind, immune bridging with post-authorisation vaccine effectiveness to demonstrate non-inferiority against an approved comparator vaccine with an original SARS-COV-2 Wuhan strain (D614G), based on pre-defined margins for seroconversion rates (SCRs) and geometric mean titres (GMTs) as stipulated in EMA and FDA guidelines, is perhaps the most logical way forward for adapted variant strain vaccines. In view of this, which variant strains should second, or third generation developers be considering?

Recent mounting evidence suggest that neutralizing antibodies are sufficient to confer protection against SARS-CoV-2 infection and later emerging strains (such as the South African B.1.351 variant strain) generate neutralizing antibodies with a higher cross-neutralization capacity against original “first wave” strains. In contrast, the original variant strains show reduced potency against emerging strains [12, 13]. Based on data from these studies which observed effective neutralization of the original virus by the B.1.351 variant infection elicited plasma, it is strongly hypothesized that variant strains can retain activity and may elicit antibodies that can protect against multiple circulating SARS-CoV-2 lineages.

Considering this, it is strongly recommended that later generation COVID-19 vaccine developers consider immune bridging trials with VOCs before marketing authorisation application (MAA), incorporating them into their development plan. This will therefore establish a comprehensive clinical development plan going forward to tackle future SARS-CoV-2 variants. An overview of a non-inferiority immune bridging approach to streamline development for late-coming COVID-19 vaccines and adapted variant vaccines is presented below in Figure 1.

How to position your late-coming vaccine?

With increased vaccination rollout of authorised vaccines worldwide, particularly in the US, UK, and Europe, what is the market for late-coming vaccines? Fortunately, there are still several avenues to exploit for the approval of later vaccines. With varying reports on the longevity of effectiveness of several vaccines, there is currently a need for “booster shots”. If a vaccine confers immunity for only a few months rather than many years, booster shots may become more regular than initially expected.

With the emergence of more virulent strains, second and later- generation vaccine developers almost have an advantage in that they can tailor their vaccine development towards tackling these variant strains. As demonstrated, these variant strains show better crossneutralization capacity against the original strains [12, 13], therefore these later-coming vaccines may become the first choice in certain regions where vaccination programs are not as well established, and vaccination rollout is slower. This opens a huge market for lower- and middle-income countries (LMIC) in Africa and certain regions in Asia and South America.

First generation vaccines have also not come without their issues. There has been major backlash against authorised COVID-19 vaccines due to unforeseen side effects, along with general apprehension due to media attention. There have also been critical manufacturing bottlenecks which have hindered the development and supply of vaccines, leading to shortages. Considering these difficulties, late coming vaccines with a comprehensive manufacturing and development plan can take advantage and present themselves as main contenders at the COVID-19 table.

So how can late developers demonstrate the efficacy of their vaccines? How should the studies be designed? If you are looking for the answer to these questions, please do not hesitate to contact our team. We have great track-record of assisting multiple COVID-19 vaccines projects at different stages of development. In the current epidemiological landscape, as the development of many vaccine technologies progressed to the authorisation stages, we also initiated designing novel, comparative vaccine development strategies to tackle the problems that the “late-comers” may encounter. 

References:

1. Forni, G., et al., COVID-19 vaccines: where we stand and challenges ahead. Cell Death & Differentiation, 2021. 28(2): p. 626-639.

2. Liu, M., et al., Innovative trial designs and analyses for vaccine clinical development. Contemporary clinical trials, 2021. 100: p. 106225-106225.

3. Earle, K.A., et al., Evidence for antibody as a protective correlate for COVID-19 vaccines. medRxiv, 2021: p. 2021.03.17.20200246.

4. Khoury, D., et al., What level of neutralising antibody protects from COVID-19? 2021.

5. EMA, Reflection paper on the regulatory requirements for vaccines intended to provide protection against variant strain(s) of SARS-CoV-2. 2021.

6. FDA, Emergency Use Authorization for Vaccines to Prevent COVID-19: Guidance for Industry. 2021.

7. Consortium, A., Points to consider for strain changes in authorised COVID-19 vaccines in an ongoing SARS-CoV2 pandemic. 2021.

8. Volz, E., et al., Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data. medRxiv, 2021: p. 2020.12.30.20249034.

9. Tegally, H., et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, 2020: p. 2020.12.21.20248640.

10. Faria, N.R., et al., Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. medRxiv, 2021: p. 2021.02.26.21252554.

11. COVAX, SARS-CoV-2 variants – Practical considerations for accelerated clinical development in light of current regulatory guidance. 2021.

12. Cele, S., et al., Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature, 2021.

13. Moyo-Gwete, T., et al., SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies. bioRxiv : the preprint server for biology, 2021: p. 2021.03.06.434193.