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The participants we need in Phase 3 trials

While everyone else can avoid exposure to COVID-19, healthcare workers have to work in high-risk environments with repeated exposure to infection. Vulnerable groups such as the elderly and those with co-morbidities have five-fold to 15-fold greater mortality when they get COVID-19 than others. Therefore, healthcare workers and vulnerable groups need to be treated as priority categories for vaccination when the COVID-19 vaccine is available.

Protecting against COVID-19

Two COVID-19 vaccines have been accepted for Phase 3 trials after passing the Phase 1 trial for safety and the Phase 2 trial for both safety and the vaccine’s ability to induce a virus-neutralising antibody with or without T-cell-mediated immunity. Vaccine-induced immunity has not yet been proven to protect against COVID-19, but the likelihood of protection is quite high for the following reasons.

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Natural infection induces both a virus-neutralising antibody and T-cell-mediated immunity. Convincing reports of reinfection by the novel coronavirus in previously infected individuals are extremely rare, suggesting that natural infection is indeed protective in the vast majority. When a vaccine candidate produces similar immune responses, the probability of it being protective against the disease is high. A vaccine that has passed Phase 2 should therefore be assumed to be protective, unless proved otherwise in a Phase 3 trial which will provide additional evidence of freedom from rare side-effects. Once cleared in Phase 3, the vaccine is registered by the drug regulatory agency and vaccination of the general public carried out as per national policy.

Interim reports on Phase 1 and Phase 2 vaccine trials from China, with an inactivated whole virus vaccine (using mercapto-ethanol instead of formalin to minimise immunological lung injury), have demonstrated immunogenicity and short-term safety. A Phase 3 trial is in progress. India is embarking on a Phase 3 trial with a similar vaccine.

The objective of vaccination is three-fold: in the short term, to protect vulnerable individuals from serious disease and death; to protect occupationally exposed individuals from acquiring and unwittingly transmitting infection to their patients and family; and, eventually, to eradicate the viral infection. The measure of effectiveness of a vaccine is how many infections and how many deaths it can prevent rather than how high the antibody titre will be, because antibodies are only surrogate markers of protection. To demonstrate that the vaccine achieves the short-term objectives, it is important that the vaccine trials include a good proportion of special groups of individuals. The twin clinical outcomes of reduced mortality in vaccinated vulnerable individuals and reduced infection rates among healthcare workers will quickly provide unequivocal clinical measures of vaccine efficacy. Under normal circumstances, Phase 3 vaccination trials include only healthy adult volunteers and once the vaccine is found to be safe and effective, small bridging studies are conducted among vulnerable subjects. However, in the pandemic situation, if vulnerable groups are deliberately included from the beginning in Phase 3 trials, using a special study design, when the trial is over we can proceed straightaway to immunising these subgroups.

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The drug regulatory agency should recognise this risk-based categorisation of the public and help design the Phase 3 trial in which vulnerable people and healthcare workers are preferentially given an opportunity to register themselves as volunteers. Obtaining information on vaccine efficacy and safety from these subgroups is of paramount importance to facilitate prioritised vaccination of those who did not have an opportunity to enrol as volunteers for the trial and those who got placebo injection.

Why healthcare workers?

There are several reasons why healthcare workers, particularly those above age 55, should volunteer for and be included in Phase 3 trials. Historically, healthcare workers have often been the first to volunteer to participate in several physiological and pharmacological studies of an experimental nature. This attitude is more appropriate now than ever before in the context of COVID-19 vaccination trials. Participation of healthcare workers will motivate and enthuse members of the general public to participate in the trial and make recruitment easier.

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The loss of many colleagues, mandatory quarantine of increasing numbers of infected healthcare workers, the struggle to cope with the escalating number of cases in the face of workforce depletion, and the worries about risk to their immediate family have eroded the morale of all healthcare workers in India. Inclusion of healthcare workers in the Phase 3 vaccine trial may prove to be the silver lining and boost the sagging morale of healthcare workers.

Healthcare workers, in particular doctors and nurses, understand controlled clinical trials and the safety features in vaccine production and would be better able to provide informed consent. Further, they will clearly understand that half the enrolled subjects receive only a placebo and therefore no one will flout personal protection norms even after receiving the vaccine trial injection.

Information on side-effects, a vital deciding factor in vaccine acceptability, is easy to collect and document if healthcare workers are part of the trial. Self-reported adverse events with relevant details can be obtained on a mobile phone platform and maintained in a computerised database.

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How do we mobilise healthcare workers to participate in the Phase 3 trial? In an astute move, the Duke Research Institute started HERO (Healthcare Worker Exposure Response and Outcomes) which encourages healthcare workers to participate in all COVID-19 clinical trials including vaccine trials. The Indian Medical Association and nursing and paramedical professional organisations, who have enrolled all members of the healthcare work force, should come together on a similar platform and encourage healthcare workers to enrol for the Phase 3 COVID-19 vaccination trials. If the vaccine is efficacious, at least half the trial participants will be protected (the other half will be in the placebo arm).

Conditions apply

Conditions apply for inclusion of healthcare workers in the trial. Those healthcare workers who have already contracted COVID-19 and who do not need the vaccine will be listed in the National Registry. Of those who have so far not been infected, IgG antibody testing will identify antibody positive subjects who do not need vaccination. Sero-prevalence of IgG antibody in healthcare workers is likely to be 30-40% as is the case currently in our metros; only the remaining proportion of healthcare workers will still be susceptible. It should be possible to accommodate these eligible subjects into the Phase 3 trial protocol without much difficulty.

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All round it would be a good idea for healthcare workers and vulnerable subjects to enrol in the COVID-19 vaccine Phase 3 trials in India. If this is to be done quickly, professional organisations, civil society, regulatory agency, the Indian Council of Medical Research and vaccine manufacturers should act immediately and allow and encourage enrolment of healthcare workers and vulnerable people in Phase 3 trials.

M.S. Seshadri is former Professor and Head, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, and currently Medical Director, Thirumalai Mission Hospital, Ranipet; T. Jacob John is former Head of the Departments of Clinical Virology and Microbiology at Christian Medical College, Vellore


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Printable version | Jun 16, 2021 1:54:03 PM | https://www.thehindu.com/opinion/lead/the-participants-we-need-in-phase-3-trials/article32459266.ece

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