In the face of the COVID-19 pandemic, the world is racing to find a safe and effective vaccine for the SARS-CoV2 virus, and industry and academic researchers have initiated clinical trials across the world to test various candidates. In upcoming blogs, we will explore the different vaccine technologies in clinical development, along with where they originated and where they might be tested and manufactured.
There are diverse mechanisms being employed across the handful of potential vaccines: inactivated virus vaccines, RNA vaccines, DNA vaccines, viral vector-based vaccines, and recombinant protein vaccines, among others.1,2 Each technology has strengths and weaknesses based on the relative track record to date. For example, older tried-and-true technologies like inactivated virus vaccines are supported by the historic safety and efficacy of several other commonly used human vaccines using this technology (like flu, polio and hepatitis A). With the existing infrastructure for manufacturing these vaccines, there may be more capacity already built for scale-up, though they may still face physical plant limitations based on the sheer volume required.3 Additionally, there are safety risks associated with the inactivated virus approach—specifically the potential for vaccine-associated disease enhancement—that will need to be understood and addressed.3
Viral vector-based vaccines have increasingly become a focus following their development for Ebola. This approach has been demonstrated both in prior pandemics in clinical trials and in gene therapy.1 Vaccines using this approach may use another virus, like adenovirus (the common cold is in this family), that has been engineered to make SARS-CoV2 proteins in the body.1 Many of the candidates using this technology are using non-replicating viral vectors, meaning these viruses can’t reproduce in humans and may require additional booster shots to provide protection. This was observed during the prior Ebola outbreak, where homologous adenovirus approaches generated high levels of immunogenicity but the effect was not necessarily as durable as desired. Some have suggested that a heterologous approach could address this issue and improve durability.17
By comparison, with newer technologies like nucleic acid-based vaccines (DNA- and RNA-based vaccines), some of the risk and difficulty of manufacturing infectious viruses can be avoided, as the small lengths of nucleic acid can be manufactured in a cell-free process without producing the whole pathogen.4 Additionally, many believe these technologies are easier to scale up for manufacturing4 and may enable the rapid production of the candidate given lower volume and physical plant requirements; however, there are no precedents for both late-stage development success and achieving commercial scale. For RNA approaches specifically, while some cite liposomal delivery for nucleic acid approaches as a potential adjuvant that can enhance immunogenicity, the relative durability of effect remains unknown.
Currently, there are 13 unique vaccine candidates in clinical trials. The majority of clinical-stage programs either originate or have development ties to the U.S. and China, with select other countries playing a key role, particularly Germany, the United Kingdom and Canada. Originating sponsors and development partners include:
- U.S.: Moderna, Inovio, Novavax (originating), Pfizer, Dynavax (development)
- China: Sinovac, Wuhan Biological Products Research Institute, CanSino, Shenzhen Third People’s Hospital (originating)
- Germany: BioNTech (originating)
- U.K.: University of Oxford (originating)
- Canada: Symvivo, Immunitor (originating), National Research Council of Canada (development)
A significant proportion of the vaccine candidates originated in China and are currently undergoing clinical testing only in China; there are at least six trials investigating three different vaccine technologies. Clinical-stage candidates to date originating from China utilize inactivated virus-based, viral vector-based, and modified antigen presenting cells (APCs) technology.
In contrast, to date the U.S. has initiated trials solely evaluating nucleic acid-based vaccines, with one recombinant protein candidate to begin testing soon. The lead U.S. nucleic acid candidates may quickly be fast-tracked through FDA approval, as we have recently seen with Moderna’s mRNA-based candidate (mRNA-1273),8 and may benefit from reduced manufacturing timelines that nucleic acid technologies could employ. Of preclinical-stage programs, both Johnson & Johnson and Sanofi are being closely followed but are not expected to enter trials until the second half of 2020.6,7
Though both the U.S. and China lean heavily on different technology platforms today, complementary approaches may be lying in wait. In China, BioNTech’s RNA vaccine—the same one that’s in partnership with U.S.-based Pfizer—is expected to be demonstrated in a local trial through a partnership with Fosun Pharma. In the U.S., a viral vector candidate being developed by Janssen may complement existing nucleic acid approaches once it reaches human trials.6
Besides safety and efficacy, there are many variables that will affect the success of the candidates and how quickly they can be brought to market across the world, including:
1. Trial design and the ability to enroll patients: Many innovative and adaptive trial designs are being explored to address this unprecedented pandemic. But as new infections decline in some geographies, some studies are being forced to shut down due to a lack of eligible new COVID-19 patients. Vaccine candidates with trials in multiple geographies may be more successful due to the potential for heterogeneity in infection rates seen across different regions and access to more potential trial participants. Companies will have to make bets based on both the science and policy direction of a country such that their eligible trial participant pool does not dry up like some of the high-profile trial closures cited above. Additionally, many trials may focus on testing the vaccine in groups at higher risk for complications from COVID-19,9 and as the number of new infections drops, statistical power and risk-benefit ratio may be more readily demonstrated in these groups where there is a higher case load. Vaccines entering the race later this year may prioritize clinical development in hot spot regions and in countries with increasing cases to enable quick enrollment.
2. Ability to successfully scale manufacturing to meet demand, both domestic and global: The relationship between development locations and manufacturing footprint differs significantly today based on where the originating sponsor is based. Chinese-sponsored programs today are relatively self-contained—both development and manufacturing are slated to take place in China. However, many of the top candidates from other regions have forged agreements and partnerships across borders, both with governments and other private companies, to fund vaccine development and expand the potential manufacturing capacity to meet both the local and global need. In the case of the U.S., it is possible those relationships may be needed to meet both domestic and global demand: Moderna (U.S.) has partnered with Lonza (U.S., Switzerland) to scale up their vaccine manufacturing, and Pfizer (U.S.) is working with BioNTech (Germany) with additional manufacturing planned in Belgium.8,14 In the U.K., Oxford’s (U.K.) deal with AstraZeneca (U.K.) to manufacture their candidate could meet domestic U.K. demand and that of other markets, while partner Serum Institute of India has suggested that production from their manufacturing deal may first go to meet local India demand.15
3. Regulatory flexibility: In light of the profound impact of the virus, regulators may assess whether approval in one geography may warrant a lightened regulatory burden for approval in other geographies. For example, Gilead’s remdesivir was granted Emergency Use Authorization (EUA) for treating COVID-19 patients in the U.S., and shortly thereafter the Japanese Ministry of Health, Labour and Welfare granted the drug approval based on “an exceptional approval pathway,” referencing the EUA and data from the U.S. trials.10
4. Geopolitical factors influencing the global import/export of vaccine supply: As the pandemic swept the globe, many countries clamped down on exports of protective medical equipment and drugs needed to fight the virus.11,12,13 As promising treatments and vaccines emerge, world leaders will continue to influence their global distribution. EU leaders have rallied to coordinate multinational funding for vaccine development,11 and the WHO has warned that “protectionism could limit the global availability of vaccines.”13 While some companies have pledged to offer access to vaccines on a not-for-profit basis, it’s unclear how prioritization and distribution of a limited global supply may play out. Serum Institute’s announcement that they will prioritize India-based demand—as well as large U.S. Biomedical Advanced Research and Development Authority (BARDA) contracts with Moderna and Janssen—suggests that countries may elect to meet domestic demand first before shipping any doses out of the country. More recently, French authorities have criticized Sanofi’s position on supplying U.S. demand first, given Sanofi’s BARDA collaboration.16 Depending on which mechanisms work, there could be an imbalance of supply globally and how that supply gets circulated.
In our upcoming posts, we will explore those factors, beginning with the development and manufacturing partnerships that vaccine sponsors are entering. For additional information about the evolving COVID-19 pipeline, study results and milestones, please visit our visual COVID-19 vaccine and treatment pipeline tracker. Check back weekly as we provide an updated view of the clinical development landscape and advancements in the search for safe and effective tools to fight the COVID-19 pandemic.
- ZS analysis of Adis, Citeline-Pharmaprojects, clinicaltrials.gov, Trialtrove and PharmCube data