Safety concerns delay vaccine approval in India

No vaccine has yet been approved for public use in India on account of inadequate data on safety and efficacy of the candidates, but that has not stopped the Central government, working with States and Union Territories, from preparing for a countrywide roll-out when the clearance comes.

Margaret Keenan, 90, becomes the first patient in the U.K. (and the world) to receive the Pfizer-BioNTech mRNA COVID-19 vaccine outside a clinical trial setting, at the University Hospital in Coventry on December 8.

THE hype and hullabaloo over the availability and distribution of the COVID-19 vaccine in India have been gathering a lot of steam in recent days, with politicians, the Prime Minister in particular, making all kinds of assurances. Three vaccine developers have sought Emergency Use Authorisation (EUA) from the Drugs Controller General of India (DCGI) for their respective vaccines: the Serum Institute of India (SII), Pune; Bharat Biotech, Hyderabad; and Pfizer-BioNTech (a collaborative venture of a drug major from the United States and a German start-up). Only Bharat Biotech’s candidate called BBV152B, or Covaxin, which it developed in association with the Indian Council for Medical Research (ICMR), is indigenous. While both Pfizer-BioNTech and the SII filed their application for EUA on December 6, Bharat Biotech put in its request on December 7.

However, none of the above is ready for a roll-out in the country any time soon, so it is too early for any kind of celebration to begin. Of course, given the background of the irrational politically motivated move of asking Indian developers to get the vaccine ready by August 15, a similar attempt to get a vaccine approved for public use by January 26, 2021, is quite possible. Speaking about India’s vaccine development at an all-party meeting on December 4, the Prime Minister said an Indian COVID-19 vaccine would be ready in the next few weeks. Echoing this statement, Health Secretary Rajesh Bhushan said at a press briefing on December 8: “The honourable Prime Minister has personally interacted with and encouraged all vaccine manufacturers and scientists…. Multiple vaccines are in different stages of development, some may get licensed in [the] next few weeks.” How could the Prime Minister even say this when on December 4 not even one developer had sought EUA from the government.

But as Frontline goes to print, the Subject Expert Committee (SEC) of the Central Drugs Standard Control Organisation (CDSCO), which is entrusted with overseeing the vaccine approval process before the DCGI gives its final stamp of approval, hit the pause button at the preliminary stage itself. The SEC reviewed the three EUA applications on December 8. According to news reports, it has sought more safety and efficacy data from both the SII and Bharat Biotech. Pfizer-BioNTech apparently has sought a little more time as its representative experts from the U.S. could not attend the meeting. According to Reuters, a source with “direct knowledge of the matter” told the news agency that the SEC would take a decision “in toto” and it was too early to say whether the applications would be accepted or rejected.

U.K. grants approval for Pfizer-BioNtech’s vaccine

Pfizer-BioNTech’s vaccine, an mRNA vaccine called BNT162b2 (“ Vaccine battle ”, Frontline , December 4), was the first to be approved globally when the regulator in the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA), granted EUA for it. Mass vaccination began in the U.K. on December 7. Pfizer was also the first to apply for EUA in India. As regards the data the SEC is seeking, it would seem that Pfizer-BioNTech would be more ready than the SII or Bharat Biotech because their phase III trials are still ongoing. In fact, the SII has not even registered with the Clinical Trials Registry - India (CTRI) for large phase III efficacy trials for its vaccine Covishield. Oxford University and the British-Swedish company AstraZeneca jointly developed Covishield, a simian adenovirus-vectored vaccine called ChadOx1-nCOV or AZD1222, and transferred the technology to the SII.

On the basis of the data from Oxford-AstraZeneca’s phase I/II trials in the U.K. and recent phase III efficacy trials in the U.K. and Brazil, the SII has been conducting only bridging studies, which involve testing for safety and immunogenicity but not for vaccine efficacy, on just 1,600 volunteers in India. This would be deemed all right given the pandemic situation and under a fast-track approval process. But the U.K. government (or for that matter any of the other three countries, the U.S., South Africa and Brazil, in which the vaccine is undergoing efficacy trials) has not approved EUA for the Oxford-AstraZeneca vaccine because of questions over the phase III efficacy trial data even as it granted approval to the Pfizer-BioNTech vaccine. The SII’s bridging phase III trials started on September 21, and volunteer recruitment for the same was completed on November 12, according to the CTRI. However, the details of the ongoing trials are not in the public domain yet.

As regards Bharat Biotech’s phase III trials (for safety, immunogenicity and efficacy) of its vaccine Covaxin (or BBV152B) on 25,800 recruits (as stated by the company in the CTRI listing), recruitment began on November 11 and is currently ongoing. A primary efficacy analysis will be carried out when the target number of 130 recruits (both vaccinees and control included) become RT-PCR (reverse transcription polymerase chain reaction) positive for SARS-CoV-2 following vaccination in a double-blinded, randomised trial (with control) using a double-dose adjuvanted inactivated whole virion vaccine (“Race for immunity”, Frontline , October 23). This interim data analysis (carried out by an unblinded biostatistician, that is, the person in a single- or double-blinded trial who knows which participants got the vaccine shot and which the placebo shot) and the safety and immunogenicity data will be presented to the CDSCO, according to the company’s statement on the CTRI listing. The phase III analysis will, however, continue beyond that as well.

Although, the Oxford Group is the first to publish details of its phase III trials in a peer-reviewed journal, which it did in The Lancet on December 9, questions still remain unanswered fully. On the other hand, even though the phase III trial data of the mRNA vaccines of Pfizer-BioNTech and the U.S. company Moderna (called mRNA-1273) are yet to be published in any peer-reviewed journal, they have put out more information in the public domain than Oxford University and AstraZeneca and perhaps due to that they seem to have gained more public confidence.

As the editorial in The Hindu on December 8 pointed out: “Lack of transparency about vaccine safety and efficacy does no good in gaining people’s confidence and willingness to get vaccinated. While Moderna, Pfizer and AstraZeneca took the extraordinary step of publicly sharing the trial protocol, the time points at which interim analysis of phase-3 trial in India will be carried out for safety and efficacy is unclear. While the U.S. FDA [Food and Drug Administration] has clearly spelt out at least 50% efficacy and stipulated a median follow-up duration of at least two months after completion of the full vaccination regimen to assess a vaccine’s benefit-risk profile for emergency-use approval, no such conditions have been mentioned by the Indian regulatory agency.”

Non-availability of ultra-cold chain

From the perspective of the Indian regulatory agency, it would be easier to grant EUA approval for the Pfizer-BioNTech vaccine because, for one, the vaccine has already got the nod from the U.K. government and, two, the company seems to have adequate data on the vaccine’s safety and efficacy. Of course, it is possible that Pfizer may be asked to conduct bridging studies in India like Oxford-AstraZeneca has been required to do. But if the Indian regulator were to take into account the delivery infrastructure needed, the evident non-availability of the required ultra-cold chain in India would effectively rule out its use in the country, especially when Pfizer has explicitly stated that its vaccine will not be available for distribution in the private markets of the world. The vaccine has to be stored at −70° Celsius in transit and in the hospital/clinic environment (“ Vaccine battle ”, Frontline , December 4).

In a recent communication, a Pfizer spokesperson stated: “If our vaccine candidate is successful, Pfizer would allocate the available doses across the countries where we have fully executed supply agreements. Once approved, Pfizer will supply this vaccine during this pandemic phase only to governments across the world based on [these] agreements, and following regulatory authorisation or approval. Given the terms of various agreements, we can confirm that the U.S., U.K., Australia, Japan, Qatar, Peru and Canada have already placed advance orders for supply of our potential COVID-19 vaccine. We remain committed to engaging with the Government of India to advance our dialogue and explore opportunities to make this vaccine available for use in the country.”

The cost of the vaccine has been pegged at about $55 a dose, and the vaccine has been found efficacious in a two-dose regimen, with the booster shot after three weeks. Although, in a recent evaluation, the U.S. FDA, from which Pfizer has sought EUA approval, found that the priming dose itself had an efficacy of 66 per cent, only a prime-boost regimen gave an efficacy of 95 per cent, the company has stated. A price at this level would be prohibitive for the Indian government to enter into an agreement with the company for distribution within the country.

Moderna’s mRMA-1273, the other front runner candidate, which does not require ultra-cold chain conditions for transportation and storage and is also priced significantly less, at $19 per dose, has, however, not sought EUA authorisation in India. Its product is largely committed for supply to the U.S. government and for U.S. citizens.

From the perspective of easy availability and affordable access in India, Oxford-AstraZeneca’s vaccine would seem to be the best bet, especially from the distribution logistics and cost point of view. Priced at $3-4 a dose—the SII too has stated that it would be supplying the vaccines to the government at around Rs.250 a dose—and with transportation and storage for up to six months at normal refrigerator temperatures of 2- 8° C, this vaccine, which has been shown to be safe and immunogenic across all age groups, would be the obvious choice. The catch, however, is that the Indian phase III trials of Covishield are not yet aimed at measuring its efficacy, and data from the parent developers’ phase III efficacy trials in the U.K., Brazil and South Africa are too confusing for the vaccine to be accepted at face value as one with an efficacy comparable to those of Moderna and Pfizer-BioNTech or at least enough to be given EUA approval. In fact, once the MHRA of the U.K. government gives the Oxford-AstraZeneca vaccine the nod for EUA, India would, in all likelihood, follow suit almost immediately.

Dosing error

Oxford-AstraZeneca’s interim analysis of its phase III trial data was based on 131 COVID-19 positive cases in a subgroup of 11,363 trial participants (“ In the final lap ”, Frontline , December 18). The trials used a double-dose regimen of a standard dose (SD) of 50 billion virion particles (5 × 1010) each given 28 days apart. Owing to some “serendipitous” dosing error, a subgroup of 2,741 participants received only about half the SD, or a low dose (LD) of 2.2 × 1010 particles as the first priming dose and received the SD as the booster. That is, they received an LD/SD combination, whereas the other 8,622 participants received the SD/SD regimen as per the stated protocol. The subgroup that got the LD/SD regimen comprised only volunteers from the U.K., while the SD/SD group had participants in the U.K. and Brazil

This mistake, according to a recently paper published in The Lancet , occurred because of a labelling error at the contracted manufacturer’s end and was discovered by the researchers in April when they found that the extent of reaction to vaccination—events such as fatigue, headache and mild fever—was much less than expected in the subgroup. However, the researchers decided to continue monitoring this group separately after modifying the trial protocol suitably in July.

Surprisingly, the researchers found in the interim analysis that the vaccine regimen of LD/SD showed an efficacy of over 90 per cent compared with 62 per cent for the SD/SD regimen. The researchers pooled the data of the two groups and stated that, as a weighted average, the vaccine showed an efficacy of 70.4 per cent. This was apparently done with the approval of the agency regulating vaccine trials in the U.K.

A scientific understanding about this puzzling result is, however, lacking. While various hypotheses have been advanced to explain this peculiar phenomenon, scientists are puzzled and unable to offer any credible theory for it. From a regulator’s point of view, use of this vaccine at the LD/SD regimen, even for EUA, cannot—and, indeed, should not—be given on the basis of data from such a small sample, argue scientists. More robust phase III trials with a much larger sample size are required for approval for public use even under EUA. Which dosing regimen is the most efficacious remains unclear.

Also, the age bracket of the subgroup of 2,741 who received the LD/SD regimen was below 55, so it is not clear whether the vaccine at this dose will be efficacious and protect those above 55. Interestingly, when the data is stratified by age, as it was in the published paper, efficacy among the adults was higher with the LD/SD regimen than with the SD/SD regimen. The number of people above 55 years only constituted 12 per cent of the 11,000 plus volunteers whose data have so far been analysed. These things might become clearer only after more data come in from the trials of more volunteers from the enrolled lot of about 24,000 people.

Other problems

Apparently, there are other problems with the Oxford-AstraZeneca data. Statisticians have questioned such an efficacy analysis of pooled data (from both the U.K. and the Brazilian arms of the trials). It is like putting apples and oranges in the same basket. In the analysis of the 131 COVID cases to give 62 per cent efficacy with the SD/SD regimen, it has not been stated how many belonged to which arm of the trial. While the vaccine would seem to work the data are not robust enough for immediate authorisation, some scientists have argued.

One positive result from the Oxford-AstraZeneca trials is the monitoring of asymptomatic infections among the participants. This would be extremely useful because asymptomatic infections are probably driving the present pandemic. Neither the Moderna nor Pfizer-BioNTech trials have any data on this aspect of COVID-19. Oxford-AstraZeneca took weekly swabs from some participants to see whether they were RT-PCR positive without developing symptoms. It was found that with the LD/SD regimen there was 60 per cent protection against asymptomatic infection. However, no data are available on this aspect with the SD/SD regimen. However, the sample size is too small to take serious cognisance of this data.

From the Indian perspective, since the SII bridging studies have been conducted with the SD/SD regimen, the question is, which efficacy figure will guide the regulator’s decision? The CDSCO and the DCGI obviously have a dilemma on their hands. In all likelihood, they will just go by the decision of the MHRA.

Baffling Statment

However, preparing the ground for a countrywide roll-out before any vaccine is identified and authorised for public use is a good thing to do in India. But, from that perspective, the following statement from Dr Balram Bhargava, Director General of the ICMR and Secretary to the Department of Health Research (Ministry of Health and Family Welfare), is baffling. In a recent Parliamentary Standing Committee report titled “The Outbreak of Pandemic Covid-19 and its Management”, which was tabled in the last week of November, Bhargava has been quoted as saying that a high-level committee chaired by NITI Aayog member Dr Vinod Paul, and of which Bhargava is the co-chair, has evolved a strategy for “Smart Vaccination”.

Under this plan, Bhargava submitted that there were mainly three groups: core group, bridge group and the general population. Once the core group is vaccinated, there is little chance of the disease spreading and there would be no need for the whole population of the country to be vaccinated. But he did not define who would be in the core and bridge groups, and the Standing Committee members, too, do not seem to have queried him on that. On June 30, the Prime Minister gave an assurance that vaccination of “anyone, anywhere” should take place and no one should be left behind.

Vaccine preparedness

In the December 8 press briefing on India’s vaccine preparedness, Health Secretary Rajesh Bhushan did give some important information in this regard, though he too said: “Every single Indian who needs to be vaccinated will be vaccinated.” He said that a National Expert Group on Vaccine Administration for COVID-19 (NEGVAC), chaired by Vinod Paul and co-chaired by him, was set up on August 7. Its other members included representatives of the relevant Union Ministries and of the State governments of Assam, Madhya Pradesh, Maharashtra, Tamil Nadu and Uttar Pradesh and technical experts. NEGVAC, according to Bhushan, is charged with providing guidance on prioritisation of population groups, procurement and inventory management, and vaccine selection, delivery and tracking.

NEGVAC, it was stated, had recommended the creation of the following priority population groups for vaccination: (1) health care workers (HCWs), totalling about one crore, in both government and private settings; (2) front-line workers (FLWs), numbering about two crore, who include personnel from Central and State police departments, the armed forces, the home guards and workers of civil defence organisations, including disaster management workers and municipal workers (excluding HCWs); and (3) prioritized age group comprising people above 50 and those under 50 years with comorbidities, totalling about 27 crore. It was, however, not clear whether these 30 crore people constituted the core group in Bhargava’s “Smart Vaccination” strategy”.

According to Bhushan, the process of creating a database of HCWs from States, Union Territories (U.Ts) and Central Ministries has already begun. He also stated that the government was carrying out preparatory activities for the roll-out of a vaccine in collaboration with States/U.Ts, which included listing of priority groups, strengthening of cold-chain infrastructure, procurement of additional vaccinators and establishing a digital platform called Co-WIN for vaccination delivery. What was not stated, however, was who would bear the cost of vaccinating these prioritised groups and whether the chosen vaccine would be available to the general population at all and, if yes, at what cost.

According to Bhushan’s presentation, the existing cold-chain infrastructure comprises 85,634 pieces of equipment for the storage of vaccines (including walk-in coolers, walk-in freezers, deep freezers and ice-lined refrigerators) at 28,947 cold-chain points across the country. The current cold-chain capacity, he stated, can store additional vaccines required for the prioritised first three crore people, that is, HCWs and FLWs. Additional requirements for cold-chain storage had already been assessed in consultation with States/U.Ts, and supply of this additional requirement was scheduled to be available by December 10, Bhushan said.

At present, there were 2.39 lakh vaccinators and 1.54 auxiliary nurse midwife personnel as part of the Universal Immunisation Programme. This strength was being augmented for COVID-19 vaccination in collaboration with States and U.Ts, the Health Secretary said. He also stated that additional procurement of needles and syringes was on track, the implementation of standard operating procedures was in the final stages and training materials and detailed implementation plans were being finalised in collaboration with States/U.Ts. Since no mention was made of ultra-cold chain transportation trucks and storage facilities, one would presume that use of Pfizer-BioNTech’s mRNA vaccine is not on the cards.

White Paper needed

But all these are just bits and pieces of information. As was pointed out in an earlier article (“ Race for immunity ”, Frontline , October 23), what is needed is a White Paper, a dynamic document that would spell out the government’s COVID-19 vaccination policy and other vaccine-related issues with updates. It should be made available on the ICMR’s vaccine portal to the public at large and have provision for accepting comments and suggestions from the public that could be acted upon.