Cecil Nick, Regulatory Consulting Services
Dr Nathalie Sohier - Global Head Infections Disease/Vaccines
Dr Sheng Feng, Real World Data Group
Following successful completion of Phase 1 healthy subjects’ studies and animal challenge tests as discussed in Part 2, a number of strategies are possible to demonstrate vaccine efficacy. Such strategies include investigating levels of clinical protection in subjects at high risk of exposure (pre-exposure prophylaxis). It has also been proposed to study immunizing subjects who have recently tested positive and are displaying no or minimal symptoms (post -exposure prophylaxis); whether vaccination at this point can still be of benefit is unclear and early introduction of anti-virals could prove a more effective strategy. Prophylactic studies could involve several approaches such as classical RCTs or ring vaccination of individuals with known exposure to a confirmed case and/or a cluster design in areas or institutions where high levels of transmission exist. Areas of high population density or where lack of adoption of social distancing measures exist represent fertile grounds for high viral transmission rates.
A more controversial approach which nevertheless is receiving serious consideration in scientific circles is a human challenge test (vaccinating a healthy subject with a candidate vaccine and then exposing the subject to the virus in order to assess protection) (Eyal et. al. 2020). Such an approach, on the face of it may seem ethically questionable, but this needs to be considered against the societal impact of the disease. In fact, risks are being taken by health care workers daily and more extremely from a societal perspective soldiers can face much higher risks in times of conflict. The risk of mortality to young healthy subjects is less than 0.1% (Monnery 2020) which is still not insignificant, but this could potentially be substantially further reduced once therapeutic interventions are available. Rapid progress in demonstrating efficacy of certain early interventions is expected with the possibility of repurposing of current antiviral therapies and particularly the development of anti SARS -CoV2 monoclonal antibodies. Obviously, all risks would need to be very clearly laid out as part of the informed consent process.
Field trials in large cohorts are necessary to support widespread use of any new vaccine. Such trials need to be conducted in areas with high levels of community spread and trial subjects need to be stratified according to potential prior exposure to the virus. This could entail a questionnaire about recent prior illnesses and serological testing although many infected subjects are asymptomatic and serological testing is reportedly not a fully reliable measure of prior exposure (Wu 2020).
As intimated above, site locations will depend on the dynamics of the pandemic, which remains highly uncertain and there will be the need to navigate to regions of active disease and steer clear of regions where herd immunity may have been established. The concept of herd immunity is itself a challenging issue as it is not clear how long such immunity would last and whether booster vaccinations would protect or exacerbate the response to second exposure.
There are currently no immunologic correlates for protection (such as identified adequate level of immune response) and as such a clinical endpoint is needed, for example laboratory-confirmed acute clinical illness. Secondary endpoints could include lab-confirmed severe illness/ lab-confirmed possible antibody-dependent enhancement (ADE) of disease / death/ immune correlates of risk and surrogates of protection (efficacy).
The design and size of field trials will be dictated by the epidemiology. Adaptive designs can be considered whereby re-sizing decisions can be driven by the virus attack rate. Randomisation between active and placebo altered as evidence of efficacy begins to emerge. The actual numbers of subjects that will need to be recruited will depend on both the attack rate and expected level of protection provided by the vaccine. In circumstances were studies are conducted in populations enriched for exposure and where attack rates could exceed 20% and where expected protection exceeds 70% about 200 subjects will provide an 80% chance of detecting significant increase in the primary outcome measure at the 5% level. On the other hand, if the attack rate were 2%, which approaches what is likely occurring over a 3-month period in many countries where epidemic COVID-19 exists, then in the region of 1200 patients would be required. However, infection control measures such as social distancing could considerably reduce this and for an attack rate of 0.1% over 50,000 subjects would need to be recruited. In these circumstances Real-World-Data (RWD) and remote monitoring become useful in the design of field trials. Mobile phone apps have been developed for tracking and monitoring healthy adults and/or mild COVID-19 out-patients capturing data such as temperature, heart rate, oxygen saturation and respiration rate.
Recognizing the critical importance to world health of the rapid availability and deployment of effective vaccines against COVID-19, WHO has issued R&D Blueprints for a phase IIb/III vaccine platform study designated the “Solidarity Vaccine Trial”. The Master protocol is in development for a large, international, multi-site, individually randomized controlled clinical trial that will enable the concurrent evaluation of the benefits and risks of promising candidate vaccine within 3-6 months of it being made available for the trial. Candidate vaccines may be added to the trial as they become available if they meet prioritization criteria (to be defined via the WHO vaccine prioritization group). The aim is to provide reliable data within 3-6 months of receiving adequate supplies from the sponsor. The proposed primary outcome will be virologic ally confirmed COVID-19 disease, regardless of severity. Secondary endpoints may include infection with SARS—CoV-2 and severe disease including death as well as supportive outcomes. Measures will be taken to assure blinding is maintained. Efficacy follow-up will include weekly contacts and blinded study follow-up will continue for least one year, although for vaccines found to be substantially protective, vaccine and placebo recipients may be unblinded sooner (WHO).
As mentioned above Real-World-Data (RWD) are useful when designing field trials that require recruitment of tens of thousands of patients. Multiple national registrations have been created, where real-time health data are being collected for assisting prophylaxis trial enrolment. A meeting of International Coalition of Medicines Regulatory Authorities (ICMRA) discussed RWE studies in COVID-19 and agreed to share data and on the critical need for global collaboration. The EMA will launch a study to build and test a system for the close monitoring of the safety and effectiveness of COVID-19 vaccines as they become available (ICRMA).
- 1. Monnert 2020 https://blogs.lse.ac.uk/businessreview/2020/04/09/adjusting-covid-19-expectations-to-the-age-profile-of-deaths/ICMRA meeting: COVID-19 Real-World Evidence and Observational studies
- WHO R&D Blue Print, An international randomised trial of candidate vaccines against COVID-19 - outline of Solidarity vaccine trial, 9 April 2020
- Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, Ling Y, Zhang Y, Xun J, Lu L, Jiang S, Lu H, Wen Y, Huang J. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. Med Rxiv in press April 2020 [not been peer reviewed, should not be used as guide to practice] https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v1