Launching a new portal devoted to vaccines for different diseases, including COVID-19, under development in the country, on the website of the Indian Council for Medical Research (ICMR), Dr Harsh Vardhan, Union Minister for Health and Family Welfare, said on September 28 that the first vaccine in India against COVID-19 would become available by early 2021.

How he could actually give such an assurance when the three frontrunner Indian vaccines, whose partial details are available on this new portal, are still in the Phase 1/2 trials stage is not clear. (Only Covishield, which is based on the Oxford/AstraZeneca ChAdOx1 vaccine that is undergoing extensive Phase 3 trials with about 10,000 volunteers in the United Kingdom, the United States, South Africa and Brazil, has been cleared for Phase 2/3 trials for which volunteer recruitment is on.)

A strategy for fast-tracking the vaccine development, as is evident elsewhere in the world, is certainly in order (although there is no public document or white paper from the government that spells out this strategy), but to make such an assertive public declaration is not in order.

According to the World Health Organisation (WHO), as on September 30 there were 192 candidate vaccines in various stages of development worldwide, of which 151 were in pre-clinical evaluation and 41 in different phases of clinical evaluation. The three Indian efforts belong to the latter group. Thanks to the portal, at least some details, if not all, of the evaluation studies on one of the indigenous vaccines developed by the National Institute of Virology (NIV), Pune, of the ICMR are now available. Since the other indigenous vaccine is a private effort, attendant proprietary information may be the reason why even basic details of the vaccine were not available on the portal.

There are a few other efforts by the Indian industry, either in-house or in collaboration with foreign institutions, but they either do not figure in the ICMR’s Clinical Trials Registry-India (www.ctri.nic.in) or the status of those efforts is not known. For example, while a recombinant BCG vaccine for COVID-19 has been registered by the Pune-based Serum Institute of India (SII) for Phase 3 trials with a sample size of nearly 6,000, even its Phase 1 and 2 clinical trial details are not yet known.

None of the three vaccines is yet to enter the most extensive, expensive and all- important multi-centric Phase 3 trials, which will involve thousands of volunteers and take long. Rushing through this phase to conclude it before a preset deadline will only end up doing more harm than good. (Covishield has been cleared for Phase 2/3 trials with just 1,600 volunteers as these trials will piggyback on the Phase 1/2 trial results of the original vaccine elsewhere.)

With several scientific and technical uncertainties, not to mention financial and ethical issues, involved in their development, production and public distribution, such a premature assurance by the Minister will only give rise to a sense of misplaced hope and false security among the public.

This is not unlike U.S. President Donald Trump’s declaration that that a vaccine would be available to the American public before November, when that country will be having its presidential election, only to be contradicted by Robert Redfield, director of the Centres of Disease Control and Prevention (CDC), at a Senate hearing on September 15, who said he did not expect the vaccine to be available before mid-2021.

Redfield also said that a mask was more guaranteed to protect than a COVID vaccine because the vaccine may not have sufficient efficacy and may not work for everyone. Redfield’s remark is equally valid for India where the trials could fail or may not show sufficient efficacy at the end of Phase 3. One only hopes that political expediency is not behind the Minister’s declaration.

According to the ICMR vaccine portal, the following are the three vaccines for COVID-19 that are undergoing trials following clearance by the Drugs Controller General of India (DCGI):

Covaxin

It is an indigenous inactivated whole SARS-CoV-2 virus vaccine that has been developed by the Hyderabad-based Bharat Biotech in collaboration with the NIV/ICMR. The vaccine, called BBV152 (with three different formulations A, B and C), has been approved for Phase 1 and 2 human clinical trials.

According to the CTRI, Phase 1 will be seamlessly followed by Phase 2 trials, which will be a randomised, double-blind, multi-centric study to evaluate the safety, reactogenicity, tolerability and immunogenicity of the vaccine in three groups of healthy volunteers who will receive two intramuscular doses of the vaccine formulations.

The sample size will be a total of 1,125 healthy volunteers, with 375 volunteers (of age 18-55)in the Phase 1 study and 750 volunteers (of age 12-65) in Phase 2 study (in the 4:1 ratio for test and control) across 12 hospital sites. The enrolmen began on July 13. The two-dose vaccination regimen, on day 1 and day 15 (of 0.5 ml each), will be intramuscularly administered.

The portal says that Phase 1 trials have been completed and that Phase 2 is currently going on. However, the portal has not provided information about the results of Phase 1 trials. It has only given results from the pre-clinical trials with small and large animals, which are positive. But these too are only in the nature of e-prints and do not seem to have been published in any peer-reviewed journals as yet. Post-trials, Bharat Biotech will also manufacture the vaccine and the company, according to reports, is targeting a manufacturing capacity of 300 million doses.

Covishield

This vaccine, as mentioned earlier, is based on the chimpanzee adenovirus vector-based vaccine developed by Oxford University in partnership with the British-Swedish vaccine manufacturer AstraZeneca called ChAdOx1/AZD1222 (‘Quest for a COVID-19 vaccine’, Frontline, August 14).

The Serum Institute of India (SII), Pune, will, under licence from Oxford University and AstraZeneca, produce the vaccine under its brand name Covishield for domestic and regional consumption. The agreement also requires the company to make a billion doses of the vaccine for low- and middle-income countries by 2021-end.

Following the DCGI approval for Phase 2/3 trials for Covishield, SII is conducting these trials jointly with the ICMR. News reports said the company recently began its Phase 3 trials at Sassoon Hospital, Pune, with 200-300 initial volunteers, although there is no confirmation on this on the ICMR vaccine portal.

Phase 2 trials had been going on since the last week of August but had to be halted on September 9 following a pause in the U.K. trials after a reported adverse reaction event on September 6 in one of the vaccinees. On September 15 the Indian trials were resumed after the company reportedly submitted recommendations of the Data and Safety Monitoring Boards (DSMBs) of the U.K. and India requesting resumption of trials.

According to the vaccine portal, these Phase 2/3 trials are observer-blinded (where only the researcher is blinded), randomised, controlled study in healthy adults to compare the immunogenicity of Covishield with ChAdOx1 and the safety of Covishield against a placebo.

A total of 1,600 eligible participants aged 18 or more will be enrolled in the study. Of these, 400 participants will be part of the immunogenicity cohort and will be randomly assigned in a 3:1 ratio to receive either Covishield or ChAdOx1, respectively. The two-dose vaccination will use 0.5 ml of the vaccine/placebo each on day 1 and on day 29. The remaining 1,200 participants from the safety cohort will be randomly assigned in a 3:1 ratio to receive either Covishield or placebo, respectively.

As mentioned before, the results of pre-clinical animal trials and Phase 1/2 human clinical trials in the U.K. trials with ChAdOx1 (Frontline, August 14) form the basis for the trials in India. The results of Phase 2 trials in India of Covishield have not been made public yet.

ZyCoV-D

This is a plasmid DNA vaccine developed by the Indian company CadilaHealthcare Ltd. Plasmids are circular double-stranded DNA molecules usually found in bacteria. But these are external to the bacterial chromosomes and can replicate independently. This is a new technology vaccine. Plasmids are used as the platform to directly deliver the antigenic determinant (its DNA sequence) into the body.

Recombinant plasmid DNA, with DNA sequence encoding for the pathogen’s antigen engineered into it, is used as the vaccine vector so that the antigenic proteins are directly produced by the human cells, thus eliciting an immune response.

According to the portal, here the vaccine candidate will be administered intradermally and the multi-centric Phase 1/2 trials (in nine sites) will compare safety and immunogenicity of the plasmid DNA vaccine against a placebo. The enrolment of volunteers of 18-55 years of age for the trials began on July 13. The sample size will be 1,048 volunteers. The portal says that the Phase 1 trials have been completed and that Phase 2 is ongoing, but no results of Phase 1 have been posted yet. The company has also not provided any information on its pre-clinical animal trials.

Distinct platforms

The above three Indian efforts use three distinct platforms for vaccine delivery. The first, Covaxin, uses the traditional approach of using the whole virus but chemically inactivated so that it does not cause any infection. The second, Covishield, uses a vector platform, a technique that has in recent times resulted in licensed vaccines for other diseases. The third, ZyCoV-D, is based on the new and emerging technology of DNA vaccines, a platform that has never resulted in a vaccine that has been licensed for public use.

Inactivated vaccines, like Covaxin, are developed by growing the whole causative virus SARS-CoV-2 in cell culture (generally on vero cells) followed by chemical inactivation.

The main advantage of this approach is that they can be produced easily but the limited yield of the virus in the cell culture and the requirement of biosafety level 3 (BSL3) facilities are the disadvantages. Of course, Bharat Biotech has the requisite BSL3 facility.

Like Covaxin, the other global efforts using this approach include ‘CoronaVac’ (originally called PiCoVacc) by the Chinese company Sinovac Biotech Ltd., other candidates being developed in China and one being developed by the Research Institute for Biological Safety Problems in Kazakhstan.

Since an inactivated virus vaccine presents the whole virus to the immune system, the responses will target not just the S (Spike) protein, the crucial part of the virus responsible for entry of the virus into human cells and causation of the disease, but also its other components, such as the matrix, the envelope and the nucleoproteins.

While three Chinese inactivated virus candidates have entered Phase 3 trials, the Indian Covaxin, the Kazakh and one Chinese candidate vaccines are in Phase1/2.

In an e-print posted on the Internet repository bioRxiv on September 12, the developers of the vaccine made a case for their choice of the whole virus platform for the COVID-19 vaccine. The availability of well-characterised vero cell manufacturing platforms with proven safety in other licensed, live, and inactivated vaccines that have been developed before has been a factor.

“Prior experience in developing inactivated [vaccines],” the developers said, “had given us the confidence to develop a fully inactivated [vaccine] with an intact virion, imperative for obtaining an antigen that will yield high immunogenicity.”

According to the authors, a well-characterised SARS-CoV-2 strain and an established vero cell (CCL-81) platform have been used to produce a highly purified BBV152 vaccine candidate on a large scale.

The platform of using a non-human chimpanzee adenovirus vector, genetically engineered to express the antigenic S-protein, has already been discussed in an earlier article (Frontline, August 14). Indeed, many of the viral-vector vaccines use adenovirus as the vector of choice (either non-human adenovirus or inactivated human adenovirus), although other inactive virus vectors have also been used in vaccine development. By expressing the S-protein, the vaccine elicits an immune response in the human host.

While in the development of viral-vector vaccines, live SARS-CoV-2 virus does not have to be handled, one of the disadvantages is that some of these vaccines are impacted and partially neutralised by the pre-existing immunity against these viruses in humans, as was discussed in the earlier article (Frontline, August 14) in the case of Chinese CanSino Biologics’ vaccine, which uses the inactivated human adenovirus5 as the vector.

The Russian vaccine Sputnik, developed by the Gamaleya Research Institute, which also uses the inactivated human viral vector platform, uses one human adenovirus (Ad5) to prime the immune response and another human adenovirus (Ad26) to boost the response. By using a chimpanzee adenovirus, ChAdOx1 vaccine, and by corollary Covishield, circumvents this problem.

ZyCoV-D is a DNA vaccine and, like other DNA vaccines in development, is based on plasmid DNA that can be produced on a large scale in bacteria. To enable them to better express in human hosts, these plasmids include mammalian expression promoters and the S gene, which is the required antigenic determinant to be expressed upon delivery.

The advantages of plasmid DNA vaccine technologies include the possibility of large-scale production in E. coli and the high stability of plasmid DNA. However, according to literature, DNA vaccines often show low immunogenicity. One of the reasons for that is the difficulty of delivering the vaccine to enable optimal antigen expression. Intradermal delivery has been found in recent years to work better as to elicit robust immune response in DNA vaccines for other diseases.

Although the company itself has provided few details of the development of the vaccine and the delivery system used, the intradermal route may have been chosen for that reason. Worldwide, four DNA vaccines, including ZyCoV-D, are undergoing Phase 1/2 trials, although the developer of the Indian candidate, Cadila Healthcare, is reported to have begun its Phase 3 trials already.

Covaxin animal trial results

Since the pre-clinical animal trial results are available only for Covaxin, we discuss them a little here. The bioRxiv paper of September 12 also reported the safety and immunogenicity evaluation of the vaccine at three antigen concentrations of 3, 6 and 9 micrograms and two adjuvants (pharmacological agents that boost the immune response) in three small animal models—mice, rats and rabbits—used in these pre-clinical trials. Aluminium hydroxide or alum is generally the adjuvant of choice for many inactivated vaccines.

But mindful of the fact that alum-adjuvanted inactivated vaccines can sometimes lead to what is known as ‘vaccine-induced disease enhancement (VDE)’ due to undesirable inflammatory response caused by Th2 (Type 2 T-helper) cells, as seen during the SARS epidemic, the authors have formulated a modified alum-based adjuvant for this vaccine that aids to suppress hyper-activation of Th2 cells as against the more desirable Th1 cells.

With this formulation of the BBV152 vaccine, the authors found elevated levels of virus-neutralising antibodies and good T-cell responses in the above animal models. In conclusion, the paper makes a case for using this formulation in its Phase 1/2 trials.

The small animal trials were also followed by the study of the vaccine’s safety, immunogenicity and protective efficacy in other animal models such as the rodent Syrian hamsters and the larger Rhesus macaques. According to the study details posted on ICMR’s vaccine portal, the former animal model was chosen as the SARS-CoV-2 was seen to replicate both in the upper and lower respiratory tracts.

The same dose regimen of the vaccine and the same Th1-biased formulation as was used in the mice-rat-rabbit study was used in the hamster study too for evaluating the immune response. The researchers found that the vaccine induced significant titres of virus-specific IgG antibodies (which also indicated a Th1-biased immune response) and neutralising antibodies.

“Post-SARS-CoV-2 infection [by challenge],” the report said, “vaccinated hamsters did not show any histopathological changes in the lungs. The protection of the hamsters was evident by the rapid clearance of the virus in the lower respiratory tract, reduced virus load in the upper respiratory tract and robust humoral response,” thus confirming the immunogenic potential of the BBV152 vaccine.

For evaluating the response in rhesus monkeys, a two-dose vaccination regimen was used on day 1 and day 15 (like it has been proposed for the Phase 1/2 human trials as discussed above), followed by a virus challenge after 14 days of the second dose.

The study found a strong immune response in the macaques as well as their protection on virus challenge. The protective report, was observed with increasing virus-specific IgG antibodies and neutralising antibody titres from the third week after immunisation.

It said: “Viral clearance was observed from the bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissue seven days after infection challenge in the vaccinated monkeys. No evidence of pneumonia was observed…unlike [in] the placebo group…Data from this study substantiate the immunogenicity of the vaccine candidate [BBV152].”

Herd immunity

Vaccines will be the quickest route to achieving herd immunity rather than a natural infection-derived one. According to the recently concluded second round of the national serosurvey, only about seven per cent of the population has been infected with the virus since the pandemic began, which implies that nearly 93 per cent of the population is still susceptible to the virus and that the nation is a long way from the fraction required for a naturally derived herd immunity.

It would certainly be useful to be informed of the results of the Phase1/2 trials of the three frontrunners to know their respective safety, potential immunogenicity and efficacy, to know what lies ahead in the road to vaccine development in the country. But, as mentioned before, there are other non-pharmacological issues as well that need to be addressed urgently much before any vaccine becomes available for the public.

In a recent paper titled ‘Economics and ethics of the Covid-19 vaccine: How prepared are we?’, published in the Indian Journal of Medical Research (IJMR), the authors Indrani Gupta of the Institute of Economic Growth, University of Delhi, and Rama Baru of Jawaharlal Nehru University, have called upon the government to come out with a white paper on vaccine-related issues and share it with the citizens.

“A separate website on the COVID-19 vaccine may be created where the white paper (which should be a dynamic document) would be uploaded and supplemented with updates from time to time. There should be scope to invite and potentially include opinions and suggestions from the public as well,” they said in the paper. While the government has done the easy part of creating a separate portal for vaccines, there is no indication of any white paper for discussion coming.

The authors said: “To date, it remains unclear what the price tag of dealing with COVID-19 has been so far… India is at the centre of the vaccine wave, leading one to presume that the government of India has a plan already drawn up on funding, production and distribution of the potential vaccine(s).” If there is such a plan, as the authors presume, there is, however, no evidence of that either.

The authors raised several important questions around vaccine development and distribution: “Which vaccines are already under production? Which companies are producing these vaccines and in what quantities? Who is going to bear the loss in case the trials fail? What will be the loss to the government if the trials do not succeed? How much has the government invested so far in vaccine trials and production? How does the government plan to procure other incidentals that would be required for a COVID-19 vaccination programme?... The government needs to reassure citizens that fast-tracking has not been at the cost of scientific and ethical values.”

Given the glaring inequities based on social determinants such as wealth, class, race, gender and religion, the authors pointed out that the questions around who gets the vaccine, how and at what cost cannot be addressed in real time, but would require months of advanced planning and structures that would have to be put in place before the vaccines become available. “With serious inequities in access to health services, will the vaccine distribution be based on different sets of parameters of ethics and justice?” they asked.



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