Cecil Nick, Regulatory Consulting Services
Dr Kenneth Swart and Dr Matthias Kruse, Parexel Early Phase
Clearly, the potential for vaccines to enhance rather than protect against infection through the two mechanisms of ADE and ERD discussed in Part 1, highlights the need for studies in animal models and it is expected that with the intense activity focused on vaccine development, more animal data pertinent to SARS-CoV-2 will become available rapidly. Indeed, regulators have stressed the need for developing mechanisms that would allow sharing of data from animal models and clinical trials to alert the global regulatory community regarding the outcomes of trials in an ongoing and timely manner (ICRMA 2020).
WHO reports that significant progress has been achieved in the development of large animal models that recapitulate mild COVID-19 disease in humans. Several laboratories across the world have shown with high reproducibility that Rhesus macaques and ferrets are infectable with SARS-CoV-2, showing evidence of virus replication and virus shedding (WHOa 2020).
At a recent Global regulatory workshop on COVID-19 vaccine development under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), it was agreed, although not unanimously, that if a platform is well characterized, it could be possible to use toxicology data (e.g. data from repeat dose toxicity studies, biodistribution studies) and clinical data accrued with other products using the same platform to support FIH clinical trials for a SARS-CoV-2 vaccine candidate. In these circumstances thorough risk mitigation strategies need to be put in place and informed consent needs to ensure that subjects are fully aware of the theoretical risks. Careful safety follow-up and frequent monitoring following trial completion is also critical (ICRMA 2020).
Animal models are critical to successful development of all SARS-CoV-2 vaccine candidates and are necessary to obtain and to characterize the immune response induced by a SARS-CoV-2 vaccine candidate before moving into larger clinical studies, so as to address the theoretical risk for SARS-CoV-2 vaccine-induced disease enhancement. Non-human primate studies would not be required (ICRMA 2020).
The Phase 1 first in human study is generally conducted as a randomized, placebo-controlled study in healthy subjects. The primary objective of such a study is to determine safety and immunogegnicity and establish a concentration-response relationship in order to select a recommended dose to take into subsequent clinical studies. A staggered approach should be considered for risk mitigation, e.g. examine the safety and response in a few subjects before the remainder of a cohort is dosed simultaneously. In general, there could be in the region of 12 – 24 subjects per cohort. If a repeat challenge is considered necessary in order to enhance immune response, this is commonly administered 21 to 28 days after the first dose.
The antibody response needs to be well characterised in terms of titres, neutralising capacity, binding capacity, antibody type, duration of response and antibody kinetics (onset, duration). In the case of subunit vaccines, potential for enhancement of response by different adjuvants may need to be studied. WHO has issued guidance to develop and standardize assays to support vaccine development, particularly to support the evaluation of immune responses and to support clinical case definition. Basic reagents should be shared to accelerate the development of international standards and reference panels that will help support the development of ELISAs, pseudo virion neutralization and PCR assays (WHO 2020). To accelerate the availability of serology tests, the FDA is permitting the development, distribution, and use of any serology test, if it is validated, results are accompanied by a list of limitations, and the FDA has been notified (FDA 2020).
One challenge in conducting healthy subject vaccine studies during a pandemic is to put in place measures to determine whether subjects have or have not had prior exposure to the virus. Serology testing is used to detect antibodies against SARS-COV-2 in the blood and provides evidence that the patient has been exposed to the virus. The SARS-CoV-2 virus spike protein contains two domains (receptor binding S1 subunit and a membrane-fusion S2 subunit) which is both required for binding to the ACE2 receptor, however only the S2 is required for cell entry. Both S1 and S2 contains domains which overlap with other Coronaviruses however the S1 domain is the most distinctly different between SARS-CoV-2 and SARS-CoV S and could be used as an antigen in SARS-CoV-2 serologic diagnosis (Okba). This requires availability of an assay for testing blood samples for two types of antibodies, anti-SARS-CoV-2 S protein IgG and IgM, using an immunoassay such as ELISA (enzyme-linked immunosorbent assay). It will also be beneficial to analyse IgA, that is present in mucosal tissues which occur in the inner lining of the lung, since IgA is known to be important for fighting respiratory infections such as influenza, and is likely to be central in coronavirus infection, too. It is further noted that such testing may be confounded by anecdotal reports that patients who have tested positive based on the reverse transcription polymerase chain reaction assay may not subsequently have detectable levels of anti -SARS-CoV2 antibodies. Clearly it is also important to ensure that subjects are protected from exposure to the virus during the conduct of the study and to differentiate responses from natural (community) exposure compared to vaccine exposure. Exposure to SARS-CoV-2 can be to some degree controlled by testing for virus, monitoring for symptoms and checking for negativity against anti-SARS -CoV-2 antibodies against antigens other than those incorporated into the vaccine. The precautions taken to minimise the risk of subjects being infected will clearly depend on the level of infection circulating in the community and may require subjects to be kept in the unit for extended periods with strict infection control measures instituted.
Following successful completion of initial healthy subject studies and animal challenge tests, several clinical strategies are possible, and these are discussed in Part 3.
- FDA Policy for diagnostic tests for coronavirus disease-2019 during the public health emergency Part D: Immediately in Effect Guidance for Clinical Laboratories, Commercial Manufacturers, and Food and Drug Administration Staff March 2020.
- ICRMA Summary Report: Global regulatory workshop on COVID-19 vaccine development. A virtual meeting, held under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), convening experts from medicines regulatory authorities, the World Health Organisation (WHO) and the European Commission 18 March 2020.
- Okba NMA, Müller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, et al. Severe acute respiratory syndrome coronavirus 2−specific antibody responses in coronavirus disease 2019 patients. Emerg Infect Dis. 2020 Jul. https://doi.org/10.3201/eid2607.200841
- WHO(a) 2020 WHO R&D Blueprint COVID-19 animal models: summary of the progress made by the WHO COVID-19 modelling ad hoc expert working group covering period Mar 15-Mar 26? Chairs William Dowling, Simon Funnell and César Muñoz-Fontela.
- WHO(b) 2020 WHO R&D Blueprint A coordinated Global Research Roadmap: 2019 novel Coronavirus Global research and innovation forum: towards a research roadmap. https://www.who.int/blueprint/priority-diseases/key-action/Roadmap-version-FINAL-for-WEB.pdf?ua=1