Covid-19: The search for a vaccine
Pandemics are striking with greater frequency primarily because of deforestation, environmental degradation, rapid urbanisation, overpopulation, migration and growing animal and human conflict. There is no herd or population immunity against new pathogens such as the Sars-Cov-2 that causes the coronavirus disease (Covid-19), and till herd or population immunity crosses 70%, it will continue to spread. In these circumstances, public health interventions in combination with an effective vaccine may mitigate the situation.
India has the distinction of creating a vaccine for a novel virus decades ago, when the Kyasanur Forest Disease was first reported from Shimoga district in Karnataka and is now endemic in Karnataka, Kerala, Maharashtra and Goa. This vaccine, though crude, is used even today. Shantha Biotech has manufactured the world’s first effective oral cholera vaccine. The vaccine has not been used in India because cholera outbreaks are rare, but it is used all over the world in emergency situations, including in Haiti and Myanmar.
The speed with which the Covid-19 pandemic is progressing leaves the world with no choice but to have an emergency-use vaccine ready within six to eight months. We cannot afford to wait for years. In the past, the Ebola vaccine has been rapidly made available. The world already has some experience with coronavirus vaccines against viruses that cause Severe Acute Respiratory Syndrome (Sars) and the Middle East Respiratory Syndrome (Mers). The platforms and proven adjuncts being used for vaccines development are established and have been used to deliver other vaccines. Since we are not starting from scratch, an early vaccine is possible.
Most vaccines are being developed to provide immune responses either using pre-fusion or full-length spike protein. The antigen is either expressed in the human body through a messenger RNA or DNA (genetic material) put through a carrier or put in a platform.
When injected into humans, the antigen is expressed and builds up an immune response. Before antigens are put into platforms, they are tested against convalescent plasma and monoclonal antibodies in-vitro, ex-vivo or in-vivo. Mice challenge and monkey challenge experiments are also done. Since neither of these is available in India, Indian companies are outsourcing to international companies or laboratories.
Special assays using ghost cells are also needed for testing of neutralising antibodies to detect adverse reactions in cells taken from lungs or bronchus.
The most promising vaccine is the LPN-RNA vaccine (messenger RNA) being developed by Moderna, which has completed its Phase-I trial with the help of Emory, and has started recruiting for Phase-II. The Phase-I data of this two-dose vaccine, given 29 days apart, is under analysis. The four-messenger RNA vaccine of Pfizer with BNTECH has also moved to phase-I/II trial.
In India, Gennova Pharmaceuticals has developed and patented a messenger RNA vaccine that is used with a carrier lipid iron oxide (LION) and an adjuvant known as GLA-SE. Experiments in convalescent serum and mouse and monkey challenge studies have obtained very high neutralising antibody titres.
A DNA-vaccine developed by INOVIO Pharmaceuticals has gone into trial in South Korea. In partnership with Cadila Pharmaceuticals in India, the US-based Novavax is using the virus-like particles (VLP) platform, which has been previously used for the papilloma virus vaccine. Using this platform, the company has marketed seasonal influenza, H1N1 and rabies vaccines in India. This vaccine is also undergoing Phase-I trial in the United States (US) and Australia.
Oxford University is using a chimp-adenovirus platform to develop a vaccine, which will be manufactured by AstraZeneca in Europe and Serum Institute in India. It is in the Phase-I trial stage. Johnson & Johnson is using adeno-26 platform and pre-fusion spike protein, which has been successfully used by them in Ebola and RSV vaccine trials. This platform is not being used by any company in India.
Aurobindo has bought a small startup from Pfizer in the US and is using a vesicular stomatitis virus platform for vaccine development, which is likely to be manufactured in their unit in Hyderabad. The other projects moving fast in India are the CSIR-funded CCMB-Bharat Biotech partnership using a killed-vaccine for which the strain was obtained from the National Institute of Virology, Pune. Zydus-Cadila in India is also in the fray with a measles virus platform. Other projects are using an attenuated viral vaccine, which is similar to the vaccines being developed in China. Immunoglobulins against specific epitopes of Covid-19 antigens will come before vaccines only 1 is available from Israel and a cocktail of 3 are available in United States and are undergoing trials (These provide passive vaccination).
There are 110-plus vaccine projects going on at the moment, with unprecedented approaches being adopted by developers. Emergency use of the vaccine is given as soon as they finish Phase-II and move to Phase-III, and mass manufacturing begins taking up the risk of failure in Phase-III. Countries in which they are situated often fund for risk reduction and provide market commitments. This has never happened before.
One of the challenges will be to determine who gets vaccinated first. There are several scenarios, one of them is to vaccinate frontline workers, doctors, health care, sanitation and delivery workers. The second scenario is to give them to children, and the last is to conduct ring vaccination around the hotspots to immunise all the contacts and the asymptomatics. The World Health Organization will provide guidance in this matter.
Even when we have a vaccine, public health measures will be equally important, including avoiding risky behaviour, keeping social distancing, working on nutrition and access to poor populations and creating a mechanism to avoid animal and human transmission.
If trials fail and a vaccine is not available in time globally, the world will have to live with this disease for a very long time.