A majority of the global population rang in 2020 unaware of the impact the SARS-CoV-2 virus would have on the world. Although spreading rapidly, the virus had very little impact on everyday life at the beginning of the year. Despite the World Health Organization’s (WHO) Director General declaring the novel coronavirus outbreak a Public Health Emergency of International Concern, many were unaware of the scale of havoc and destruction this virus would cause. As we all now know, COVID-19 significantly changed the course of history, impacting almost all aspects of modern-day life once taken for granted.

While working practices and lifestyles may have changed for us individually, globally we have seen an extensive shift within the pharmaceutical industry. During this time, we have seen unprecedented acceleration in vaccine development, as some of the world’s biggest pharmaceutical and biotech companies turned their attention to finding a solution to tackle the threat of SARS-CoV-2. Many companies pivoted their research and development (R&D) efforts, investing in new platforms and technologies in the race to find an efficacious vaccine or treatment that would save lives. This fast-track vaccine development in a public health emergency has also been supported by early scientific advice from regulators and researchers within governmental agencies, to help accelerate development and by applying the extensive knowledge on vaccine production gained with existing vaccines.

It’s been well over a year since the first vaccine for COVID-19 came to market, and yet according to figures from WHO, there are almost 350 vaccines worldwide either in pre-clinical or clinical development.^1,2 Many companies including GSK, Novartis and Janssen all have candidates in their pipeline. However, with vaccine uptake on the rise and restrictions easing in countries, many people are wondering if the pandemic is “over.” What does that mean for an industry that has focused so much time and resources on SARS-CoV-2 R&D? Will they need to pivot their focus once again?

The evolving SARS-CoV-2 R&D landscape

The global pharmaceutical and biotech industry have made significant strides in the fight against COVID-19 over the past two years. And clinical research organizations (CROs) have been integral to that success. CROs have had to adapt and develop more diverse assays and ensure they accommodate all sponsor needs when testing candidates. These generic assays needed to be regulated in terms of antibody and cellular response measurements, but scalable as operations expanded.

Many CROs developed their own assays, so there were a lot of solutions available and in competition, but nobody had the gold standard. The Bill & Melinda Gates Foundation (BMGF) selected a provider to serve as their reference laboratory, entrusting the CRO to deliver a strategic role in helping to bring about a paradigm shift involving more open collaboration and communication between stakeholders. Although this presented challenges at the outset, it meant all labs were using standardized assays, enabling more readily and easily available comparisons with reproducible quality results.

The extent of companies’ investment in the space is clear evidence that SARS-CoV-2 research efforts will continue for several years to come. Although some are celebrating getting back to a “normal life”, the potential for new and potentially dangerous variants to emerge is high as we continue to see strains of concern appear.

In fact, we know that viruses constantly change through mutation and sometimes these mutations can result in a new variant of the virus.³ However, nobody could predict the severity of the variants we have seen. 

Governments now have well-established processes for surveillance, for example the Centers for Disease Control and Prevention monitors all variants circulating in the United States. The emergence of variants posing an increased risk to public health prompted the characterization of specific Variants of Interest (VOIs) and Variants of Concern (VOCs), that are recognized by WHO, to prioritize global monitoring and research efforts, and inform the ongoing pandemic response.⁴

In order to develop assays to keep up with the multiple variants in active circulation, a CRO has no choice but to adapt. Multiple sponsors approach their CRO partners to test their vaccines. With several variants at play, this creates more work to generate the data needed for a single sample, so CROs need to deploy multiple assays to keep pace.

Across the industry we have seen a huge demand from sponsors for antibody and neutralization response assays. However, to deliver these, the industry needs access to critical reagents. To accelerate their R&D, a sponsor must identify a partner that has their own critical reagent manufacturing team. This unique team of researchers has decades of experience and can develop critical reagents in-house at scale and under control, enabling a ready supply for relevant network(s) and a quicker turnaround than those CROs who need to source reagents via a commercial vendor. Collaborations such as the BMGF and the Coalition for Epidemic Preparedness Innovations (CEPI) have enabled selected CROs to also benefit from centralized expertise, allowing development of these critical reagents at a faster pace than through other methods.

So, it’s clear that R&D still has a significant role in the ongoing fight against COVID-19.

Opportunities requiring R&D support

Many vaccines are designed to block the entry of the virus to the target. SARS-CoV-2 tags the angiotensin converting enzyme-2 (ACE-2) receptor to cells which allows it to infect humans. Therefore, when designing vaccines many developers aim for the spike protein, as the primary target on top of the virus. However, variants are changing an entire virus and even modifying the epitopes at the surface of the spike protein, so we may need to reconsider the strategy to develop more efficient vaccines.

There is the possibility we may see multiple coronaviruses (for example, Middle East Respiratory Syndrome (MERS)/SAR-CoV-2) crossing each other. The fear is this could result in the cross reactivity of both viruses to create a “super virus.” One proactive approach to addressing this is to explore vaccines targeting not only SARS-CoV-2, but also other circulating coronaviruses with the aim to have a pan-coronavirus vaccine.

Of course, it’s expensive to shift, but there is a public health need to address this from a pan-coronavirus perspective. Each time we have a possibility of a new super virus we will have to revisit the next generation of vaccines making sure they are more efficient and effective with broad spectrum coverage. Therefore, we need to target something that will cross over all the variants, which, in turn, adds to the complexity of having assays being readily available for sponsors. This strategy could aid the longevity of the vaccine effectiveness to reduce the frequency of boosters. In comparison, the initial dose of the Polio vaccine and boosters are spread out over six years. Never in history have vaccines for one virus been given this close, and so in the future we may need a more universal vaccine.

National monitoring studies are ongoing and represent another important area where R&D can play a role.^5,6 Ensuring vaccine efficacy through testing is paramount to support these important surveillance studies.

Long-term studies and additional populations

There also remains a need to initiate studies to understand the long-term effectiveness of COVID-19 vaccines and their potential impact on other existing vaccines (for example, the influenza or measles, mumps, rubella and varicella [MMRV] vaccines). Importantly, despite the excitement for the vaccines, efficacy studies in additional populations such as in pediatrics and those with comorbidities, are still required.

Recently, Oxford University announced the launch of a study to evaluate the effects of new variants on pregnant women and newborns, as well as COVID-19 vaccination effects on complications during pregnancy and after birth.⁷ Despite the growing body of evidence regarding the dangers of COVID-19 during pregnancy and the efficacy and safety of COVID-19 vaccines during pregnancy, countries have been recording alarmingly low rates of vaccination among this high-risk group.⁶

Looking across the landscape, medical societies representing immune-compromised populations due to comorbidities are pushing for further assessment of the need for additional boosters or the development of guidelines for specific patient populations. Bodies like the American College of Rheumatology have announced updated guidelines for a potential fourth vaccine dose if required for high-risk rheumatic disease patients.⁸

Post-approval efficacy studies provide a role for CROs to support.^9-11 Clinical trials are designed to cover a minimum of one year after the trials have taken place. CROs are deeply involved in continuing to test those trial volunteers multiple times over those months that follow, as a key part of any vaccine is determining how long it’s effective and when a booster might be needed.

Following vaccine approval in the adult population, we’re seeing a shift back to CROs to support with studies in specific populations including the elderly, different genders, ethnicity, maternal as well as in pediatric patients. There is significant opportunity here for SARS-CoV-2 research, with governments’ desire to ensure as much of their populations as possible can have some level of protection from the risk of COVID-19.

Notably, this practice is common and transcends SARS-CoV-2 R&D. For example, PREVNAR 20 came to market in 2021 with the goal of providing a vaccine option for adults and pediatrics, however currently it’s only approved in the adult population for the prevention of pneumonia. The manufacturer has initiated ongoing trials in younger age groups,¹² with a goal to expand its clinical program through additional studies to support new formulations, boosters for the immunocompromised and so on.

Collaborations at the center

R&D is integral to the development of new therapies to prevent and manage COVID-19 and this must continue to ensure we can respond to and manage the ongoing threat of this disease. Central to this idea, is the ongoing need for collaboration which has underpinned partnerships between biotechnology, pharmaceutical companies, research institutions as well as CROs.

Across the industry, we have seen key non-governmental organization (NGO) partnerships such as CEPI, which has established a global network of laboratories transferring viral functional assay methods and reagents worldwide for rapid vaccine development. The BMGF has also worked with stakeholders, investing in deep technical expertise and novel platforms for vaccine development to accelerate innovation for better, faster and more affordable vaccines.

Looking ahead

Despite the successes to date, there remains many fruitful opportunities within R&D. As we have seen, partnerships and collaboration between CROs and other stakeholders are key and can support industry’s ongoing responsibility in vaccine development to ensure efficacy and safety. By leveraging the medical and scientific expertise of those at the forefront of assay standardization, NGOs, pharmaceutical and biotechnology companies can access agile solutions and platforms that can support SARS-CoV-2 R&D. These could include assay libraries for infectious diseases and networks of clinical testing laboratories that can help facilitate trials getting timely access to the right assays to optimize success.

A CRO with a diversified portfolio of researchers that can handle the workload of SARS-CoV-2 alongside other infectious diseases is important in this success. There has been increased interest in the viral neutralization assay, measurement of the total antibody being produced, as well as in the production of key reagents that can be disseminated across different networks or directly to sponsors. Cellular responses are also of interest to sponsors. We have seen a vaccine can sometimes create a cytokine storm where the level of antibodies is high. The cytokine storm is triggered for cytokine measurement, so there are assays to measure these cellular responses.

CROs that have widespread and longstanding expertise in the area of vaccine development can rapidly adapt to the next development in SARS-CoV-2 R&D, acting as an extension of a sponsor or partner’s laboratory.

Much is still not known about COVID-19, but with every day that passes we continue to learn more about the virus and how it’s driving infections across populations. As we look ahead, we can be certain that COVID-19 will play an important part in our future, and that investment in the space will yield long-term successes. Together we can unlock the potential of vaccines and continue to tackle new challenges to secure a path forward for living with this disease and supporting populations who continue to struggle. 

References

1. Pfizer press release. Pfizer and BioNTech Achieve First Authorization in the World for a Vaccine to Combat COVID-19. Available at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-achieve-first-authorization-world. [Last accessed: April 2022].
2. World Health Organization (WHO) website. COVID-19 vaccine tracker and landscape. Available at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. [Last accessed: April 2022].
3. Centers for Disease Prevention and Control (CDC) website. COVID-19 – what you need to know about variants. Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/about-variants.html. [Last accessed: April 2022]. 
4. World Health Organization (WHO) website. Tracking SARS-CoV-2 variants. Available at: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/. [Last accessed: April 2022].
5. Gov.uk website. COVID-19 vaccine weekly surveillance reports (weeks 39 to 10, 2021 to 2022). Available at: https://www.gov.uk/government/publications/covid-19-vaccine-weekly-surveillance-reports. [Last accessed: April 2022].
6. Gov.uk website. PHE monitoring of the effectiveness of COVID-19 vaccination. Available at: https://www.gov.uk/government/publications/phe-monitoring-of-the-effectiveness-of-covid-19-vaccination. [Last accessed: April 2022].
7. University of Oxford website. News. Global study launched to evaluate effects of COVID-19 variants and vaccination in pregnancy. Available at: https://www.ox.ac.uk/news/2022-02-15-global-study-launched-evaluate-effects-covid-19-variants-and-vaccination-pregnancy. [Last accessed: April 2022].
8. American College of Rheumatology (ACR). COVID-19 Vaccine Clinical Guideline Summary for Patients with Rheumatic and Musculoskeletal Diseases (v5; revised February 5, 2022). Available at: https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf. [Last accessed: April 2022].
9. Clinicaltrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/NCT04796896. [Last accessed: April 2022].
10. Clincaltrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/NCT04816643. [Last accessed: April 2022].
11. Walter EB, et al. Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age. NEJM. 2022;386:35-46. DOI: 10.1056/NEJMoa2116298.
12. European Pharmaceutical Review. Promising results for COVID-19 and pneumococcal vaccine co-administration. Available at:  https://www.europeanpharmaceuticalreview.com/news/167524/promising-results-for-covid-19-and-pneumococcal-vaccine-co-administration/. [Last accessed: April 2022].

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Luc Gagnon, PhD, Vice President of Vaccine Sciences at Nexelis, leads scientific and operations to support vaccines and biologics throughout all phases of clinical trials. Luc brings over 20 years of experience in several biotech, CRO and pharmaceutical companies to his role, including extensive expertise in ligand binding and microbiology/virology functional assay development, qualification and validation.