The catastrophic impact of COVID-19 pandemic on millions of lives and the world economy has compelled the pursuit of a protective panacea – a vaccine – mandatory. Over 150 vaccine candidates of different types – live-attenuated vaccines, inactivated vaccines, subunit vaccines, virus-like particles, viral vectors and DNA and RNA vaccines are under development. The need for speed in vaccine development during pandemic requires fast-tracking of clinical trials. However, this approach may leave important questions concerning efficacy and safety unanswered.
The safety of a vaccine for COVID-19 is a critical consideration because of its possible wide and universal usage amongst diverse populations. Based on the data from related coronaviruses – SARS-COV and MERS-COV, there is a concern that the new vaccine might potentiate SARS-COV-2 infection and cause COVID-19 vaccine-associated Enhanced Respiratory Disease (ERD) in vaccinated individuals. This can occur due to immune enhancement caused by 1) antibody-dependent enhancement of infection and 2) skewing of the cellular immune response. At present, there is limited understanding and knowledge of the potential risk of COVID-19 vaccine-associated ERD. The US FDA recommends that a company should conduct animal studies to address the potential for vaccine-associated ERD, ensure safety of healthy volunteers in Phase I clinical trials by adequate risk mitigation strategies, and plan long term safety monitoring for ERD during clinical trials.
In early phase trials, SARS-CoV-2 binding and neutralising antibody titres are measured to guide the selection of vaccine doses and for assessing efficacy. However, the ability of these antibodies to predict clinical efficacy is uncertain. As conventional laboratory strains of mice are not susceptible to SARS-CoV-2 infection, transgenic mice or non-human primates have to be used for developing models. A single vaccination with ChAdOx1 nCoV-19 – an adenovirus-vectored vaccine – induced an immune response demonstrated by the detection of virus-specific neutralising antibodies and prevented pneumonia in all rhesus monkeys challenged with SARS-CoV-2. However, the correlation between antibody titres and protection against Covid-19 disease can be confirmed only in large clinical trials, which should demonstrate the prevention of COVID-19 in thousands of participants. Recent data showing a rapid decline of antibody levels in SARS-CoV-2 infected patients has implications for the duration of protection and dose regimen of the vaccine.
Current phase I trials of vaccines are conducted in adults between 18 to 55 years. In late-phase trials, the inclusion of diverse populations – the elderly, individuals with medical comorbidities, pregnant women, women of childbearing potential and children – will be essential. Immunosenescence – declining immune function and depletion of adaptable T cells in the elderly — which makes them susceptible to a greater risk of severe COVID-19, may lead to poor response to vaccines. The elderly may require a high-dose COVID-19 vaccine for effective protection as in the case of other influenza vaccines. In the mRNA-1273 vaccine phase I, participants in a higher, 250-µg dose group reported a higher proportion of severe systemic adverse events. Rapid vaccine development without the availability of in-depth research on viral biology and the host response poses a major challenge for the scientists in ensuring the safety and effectiveness of the vaccine for the pandemic affected population.