Making dead kill live virus – the inactivated Covid-19 vaccines

By Dr Lalit Kant

Recent news of the Haryana Health Minister who volunteered to be part of the Bharat Biotech’s COVID-19 vaccine (Covaxin) trial and tested positive for Coronavirus has put the spotlight on inactivated vaccines.

Amongst the vaccines likely to become available in India against Covid-19 early in 2021 is this indigenous vaccine being developed by Bharat Biotech International Limited, (BBIL), Hyderabad in collaboration with the Indian Council of Medical Research (ICMR), New Delhi. The candidate is an inactivated whole virion vaccine.

Most of the vaccine manufacturers based in Western countries are employing ‘smart’ and ‘sexy’ newer technologies to develop vaccines against SARS CoV-2 virus. Be it mRNA technology (Moderna and Pfizer/BioNTech) or genetically engineered adenoviruses (AstraZaneca/Oxford University and Russia’s Gamaleya Research Institute of Epidemiology and Microbiology). There are a few manufacturers notably in India, China, Kazakhstan which are pursuing an old, trusted, and time-tested approach to make a vaccine against new corona virus – using an inactivated/ killed virus. First tried successfully in 1930s, unlike the mRNA or the adeno virus carrier strategy, the inactivated approach has a solid track record. It has to its credit development of vaccines such as for influenza, cholera, plague, rabies, Hepatitis A, polio (IPV) etc.  The vaccine efficacy of inactivated vaccines has traditionally been between 60 and 70%.

The approach of making an inactivated vaccine is remarkably simple. Isolate the virus from a sick/infected person, grow it in the lab, kill/inactivate it, purify, add an adjuvant, and the vaccine is ready! Its storage is also not a problem, temperature of the household refrigerator (+2 to +8°C) is all that is necessary. Refrigeration at sub-zero temperatures is not required. When injected in the humans, inactivated vaccines produce immunity.  Because the virus is dead, they interact with the immune system differently.  The immune response to live and newer vaccines is similar to encountering the virus itself resulting in development of humoral (antibodies) and cellular immunity (mediated by T lymphocytes). Inactivated vaccines produce antibodies but show little or no cellular immunity. Because killed or inactivated viruses can’t replicate, they tend to provide a shorter length of protection than live vaccines, and are more likely to require boosters to create long-term immunity.  Adjuvants are added to trigger a strong immune response. However, adjuvants can cause more local reactions (such as redness, swelling, and pain at the injection site) and more systemic reactions (such as fever, chills and body aches) than non-adjuvanted vaccines. Traditionally aluminium based adjuvants like the aluminium hydroxide, aluminium phosphate have been used to trigger strong humoral immunity but little or no cellular immunity.  Newer adjuvants are now available which help to even elicit cellular response and make the protection stronger and longer.

The inactivated approach offers some distinct advantages. The greatest one being that there is no risk of inducing the disease as the virus has been inactivated. The viruses can be rapidly grown in the lab and scaled up using well established infrastructure and methods. There are very few safety concerns. Inactivated vaccines are easy to store and transport as can be done in normal refrigerator temperatures. Because the whole virus is presented to the immune system, it is likely to target not only the spike protein of the SARS-CoV-2 but also the matrix, envelope and nucleoproteins. These vaccines therefore express a wide range of viral antigens. In general, two doses given at interval of 14 days can give antibody reaction in 4 weeks. On the down side, the inactivated vaccines produce mainly humoral immunity (antibodies), invariably require multiple doses, and often require an adjuvant. Corelates of protection afforded by inactivated vaccine are also not known as of now.

China produced the world’s earliest inactivated SARS CoV-2 candidate vaccines. Sinovac Life Sciences, Beijing developed CoronaVac, and the two branches of China National Biotec Group (CNBG) viz. Wuhan Institute of Biological Products and the Beijing Institute of Biological Products affiliated to the China National Paharmaceutical Group (Sinopharm)  have developed ‘SARS-CoV-2’ vaccine and ‘BBIBP-CorV’ vaccine respectively. Though the Phase I and II studies in China were completed prior to August 2020, only recently have the findings been published in peer reviewed scientific journals. However, no data on Phase I and II of Bharat Biotech’s vaccine is available in public domain. 

Results of studies in China indicate that the vaccines have a favourable safety profile – well tolerated with no vaccine related serious adverse events. The most common adverse reaction was site pain, followed by fever which was mild and self-limiting. The vaccines have been administered in two doses. Longer the interval between doses larger is the immune response – 28-day interval was better than 14 days. In general, the neutralizing antibodies have appeared nearly 2 weeks after the second dose.  Younger individuals (18-39 years) show higher antibody response than in those between 39-59 years. Only one study has also included volunteers older than 60 years – the most vulnerable group for SARS-CoV-2.  It is seen that the older people had lower rates of solicited adverse events than the younger group. In both age groups the vaccine was similarly immunogenic. 100% sero-conversion was reached earlier in groups 18-59 than in those over 60 years. Not only did the immune response take longer to develop in those over 60 years but antibodies levels were comparatively lower than in younger group. It has also been shown that neutralizing antibodies induced in a study cam neutralize multiple SARS CoV 2 strains – indicating the ability to protect against other strains as well.

Chinese regulators appear to be satisfied with the data of animal studies and the safety and immunogenicity data from Phase I and II trials. Both Sinovac and CNBG have received emergency use authorization in August 2020 to vaccinate populations outside the clinical trial.  According to the CNBG, hundreds of thousands of people in China have received its vaccine – healthcare workers, pandemic prevention personnel, border inspection personnel and the like.  According to CNBG it has not received any report of severe adverse reaction.  And no infection has been reported from vaccinees working in high risk areas.  UAE and Bahrain have also authorized emergency use of these vaccines in September 2020. It is being given to frontline health workers, teachers, police and customs officials. 

The Bharat Biotech’s vaccine appear to have an advantage over the Chinese vaccines in its composition. Instead of using the traditional aluminium hydroxide as an adjuvant it is using one such adjuvant called Toll Like Receptor 7/8 (TLR-7/8). This known to enhance not only humoral but also cellular immune responses. The inactivated vaccine formulation containing TLR7/8 agonist adjuvant was used in pre-clinical/ animal studies in Hyderabad. It has shown to induce Th1 biased antibody responses with elevated IgG2a/IgG1 ratio and increased levels of SARS-CoV-2 specific IFN-γ+ CD4 T lymphocyte response.

Clinical trials Phase III with inactivated SARS-CoV-2 have started for the three Chinese and the one Indian vaccine. The CNBG vaccines are undergoing trials in Egypt, Jordan, UAE, Peru, Argentina and Morocco. While the Sinovac is being tested in Brazil, Indonesia, and Turkey. The earliest trials were started in July 2020. Many of them would be nearing completion. The BBIL trial involving 26,000 volunteers was started in India in November 2020. The results of the Phase III trials of CNBG vaccines are expected any time now, and are likely to provide information on whether this vaccine is safe and efficacious against Covid-19 infection, and for how long the protective effect is maintained.  The Bharat Biotech’s vaccine would also give information to know whether its vaccine is capable of inducing and maintaining virus specific T-cell responses which are crucial for viral clearance if neutralizing antibody-mediated protection is incomplete.

It is not known whether the Haryana Minister received the placebo or the vaccine, since it is a double-blind trial. Even if he received the candidate vaccine, he got only the first dose. The trial vaccine can offer protection only two weeks after the second dose.

The writer is Dr Lalit Kant MD infectious diseases and epidemiologist