Vaccine confusion

India and COVID-19: Government's vaccination drive a total mess

Print edition : February 12, 2021

A consignment of 1,50,000 doses of Covaxin arrives in Bhopal on January 22. Photo: A.M. FARUQUI

At an assembly line for manufacturing Covishield in the Serum Institute of India, in Pune on January 22. Photo: AFP

Harsh Vardhan, Union Health Minister, displays a vial of Bharat Biotech’s Covaxin at the All India Institute of Medical Sciences in New Delhi on January 16. Photo: Bloomberg

Randeep guleria, Director of AIIMS, New Delhi, receiving a dose of Bharat Biotech’s Covaxin vaccine on January 16. Photo: Bloomberg

The government’s vaccination drive has been fraught with deficiencies in communication and delivery of doses, along with doubts regarding Covaxin’s efficacy, leading to hesitancy and low turnouts.

It’s a mess, a regulatory and operational mess. That is the short and pithy description of the ongoing COVID-19 vaccination drive launched by Prime Minister Narendra Modi on January 16.

After the messed-up approval process for Restricted Emergency Use (REU) of the two vaccines being manufactured in India—Covishield by Serum Institute of India (SII) and Covaxin by Bharat Biotech International Ltd— during the January 1-3 period (Frontline, January 29), which violated the Union Health Ministry’s own guidelines for such approvals, the first phase of the mass vaccination drive targeting 10 million health care workers (HCWs) and 20 million front-line workers (FLWs) has all the signs of being another mess.

Just as the approvals had triggered a lot of criticism from the scientific community and public health experts, the ongoing vaccine campaign, too, has attracted considerable controversy.

In his press briefing on January 12, Health Secretary Rajesh Bhushan stated that SII would be supplying 11 million doses of Covishield and Bharat Biotech 5.5 million doses of Covaxin for the first phase of the vaccination drive, and that all the doses would be procured by January 14.

Also read: Politics behind Covid vaccine rollout in India

While all the States and Union Territories would receive Covishield for implementing the drive, only 12 States would receive Covaxin. The reason for this differentiation and the basis on which the 12 States have been identified are not clear. Is it because the other States and Union Territories refused to accept Covaxin? That would, however, seem unlikely because the entire campaign is being driven by politics at the Centre.

Cost of vaccine

Of the 5.5 million doses, Rajesh Bhushan said, Bharat Biotech would be providing 1.65 million doses free of cost to the government and the rest would be priced at Rs.295 a dose. Thus, the cost of the vaccine effectively works out to Rs.206 a dose. Covishield, on the other hand, was priced at Rs.200 a dose. Rajesh Bhushan also said that the cost of the first phase would be borne entirely by the government. Subsequent news reports clarified that the money for this would be paid out of the controversial PM Cares Fund. It should be noted that these are prices for the supplies to the government. When sold in the open market to the public at large, the cost would be quite different; for example, SII has already indicated that Covishield would cost Rs.1,000 a dose.

At the time of approval of the two vaccines by the Drugs Controller General of India (DCGI) on January 3, Covishield, the vaccine being manufactured by SII under technical collaboration with the British-Swedish multinational AstraZeneca, was yet to be supported by data of its bridging safety and efficacy trials on 400 participants as had been required earlier by the Subject Expert Committee (SEC) of the Central Drugs Standard Control Organisation (CDSCO).

According to a source who requested anonymity, the company had submitted data on 185 participants only. It had also not put out any data of its safety and immunogenicity bridging studies in the public domain. Covishield’s approval was based largely on the safety, immunogenicity and efficacy data obtained from Phase 1/2/3 trials conducted abroad and published by Oxford University, the vaccine developer. These trials have shown 62 per cent efficacy with a two-dose regimen administered with a four-week gap.

Also read: COVID-19 vaccine poses both challenge and opportunity

But these data too have problems, with the United States Food and Drug Administration (FDA) openly stating that it would not authorise emergency use based on existing data. It is not clear if the SEC/DCGI had shown due diligence in going through the overseas data that had been submitted with its applicability in India in view.

As far as Covaxin is concerned, Bharat Biotech, which developed it in collaboration with the National Institute of Virology of the Indian Council of Medical Research (ICMR) in Pune, has submitted safety and immunogenicity data from the extensive Phase 1/2 trials to the SEC, but it was yet to provide any safety and efficacy data from its ongoing large Phase 3 trials.

Bharat Biotech’s Phase 3 trials, which aim to enroll 25,800 volunteers (it has already recruited 22,500 participants), are being handled by a third agency, a U.S. multinational called Iqvia that specialises in clinical trials the world over. The results of these trials will not be available before March, Bharat Biotech has said.

Clinical trial mode

The government had granted approval to Covaxin for REU with the proviso that it would be administered in ‘clinical trial mode’.This strange new phrase has baffled clinicians, immunologists and doctors, and, significantly, the vaccine manufacturer, too. Krishna Ella, the chairman of Bharat Biotech, said this in as many words during a press briefing on January 4 that he himself needed to understand what that phrase meant. Krishna Ella also could not answer a query from the media whether the ‘clinical trial mode’ vaccination during the initial phase of the campaign would be registered as an independent clinical trial with the Clinical Trial Registry of India (CTRI), besides the already registered Phase 3 trial that is ongoing. It is also not clear if Bharat Biotech subsequently got proper clarifications from the Health Ministry about how this mode would be implemented.

Also read: Safety concerns delay vaccine rollout in India

Satyajit Rath, an immunologist from the Indian Institute of Science Education and Research (IISER), Pune, said: “There… is… absolute lack of transparency and information availability on the part of the regulatory authorities, meaning the government.”

During a discussion on the issue for the news website Newsclick, he said: “They have not clarified what they mean by approval in ‘clinical trial mode’, how they want this ‘clinical trial mode’ to be operated, what sort of data [is to be collected], what sort of consent process [is to be followed], what sort of analytical approaches [have to be employed], none of these has been clarified.”

Interestingly, after having announced that Covaxin will be given only in the ‘clinical trial mode’, a media report quoted Balram Bhargava, Director General of the ICMR, as saying that the council was talking to Bharat Biotech on working out an appropriate protocol for delivering the vaccine in that mode.

It is quite bizarre that the government should announce a public vaccine delivery mechanism without devising a protocol and putting it in place. It is pertinent to note that the CTRI website does not reflect the registration of this ‘clinical trial mode’ vaccination drive at all. So, what kind of a trial is it since it is mandated by law to register all clinical trials? As Gagandeep Kang, the noted clinician and vaccinologist from the Christian Medical College, Vellore, said: “Either we have a clinical trial or we don’t; I just don’t understand this.”

Faced with a barrage of criticism like the above from scientists and public health specialists, the Health Ministry released a statement on January 14, two days before the vaccine rollout for priority groups in the first phase.

The statement, which was signed by T.D. Dogra, former Director of All India Institute of Medical Sciences (AIIMS), New Delhi, and endorsed by 48 other former and in-service medical specialists from different institutions, said: “We are…. shocked to notice the irresponsible statements by vested interests in print, electronic and social media, who are defaming Indian scientific community and casting aspersions upon its integrity by making politicised statements doubting the recent research in the field of COVID-19 vaccines. Such reprehensible utterances are causing huge credibility crisis for the Indian scientific community who have devoted their lifetimes to make India a name to reckon with in export of vaccines all over the world.”

Significantly, the letter did not offer any explanation for approving a vaccine without Phase 3 data or for the phrase ‘clinical trial mode’.

Scientists’ statements

Negating this broad-brush description of the entire community of scientists in the above statement, on the same day 13 scientists, including Partha P. Majumder, president of the Indian Academy of Sciences, Bengaluru, wrote to the editor of the The Telegraph newspaper in their personal capacities that voiced the contra view.

In the letter they said: “We express our concern about the inadequacy of publicly-available information on which the approvals to initiate the vaccine campaign have been issued by the national regulatory authorities. A greater degree of transparency prior to the start of the vaccination programme is essential. This is especially true for Covaxin…. Providing a vaccine without adequate efficacy data can lead to a false sense of security among vaccine recipients. In addition, articulation of a clear and consistent policy of making publicly available relevant data, and the approval pathway adopted by the Government of India, is required for other [COVID-19] vaccines in development to ensure rapid access to safe and efficacious vaccines both for our citizens and for the rest of the world.”

There were also contradictory statements about the ‘clinical trial mode’ from different government health officials, indicating that they themselves were not clear about what the phrase meant. These have only added to the prevailing confusion in the public mind. Soon after the vaccines’ approval, Randeep Guleria, Director of AIIMS, who is also a member of the National COVID-19 Task Force, told the ANI news agency that Covaxin could be used as a backup for now.

Also read: Oxford vaccine enjoys advantage

He said: “In an emergency situation when there is a sudden increase in cases and we need to vaccinate, the Bharat Biotech vaccine will be used. It can also be used as a backup when we are not sure how efficacious the Serum Institute vaccine is going to be.”

However, on January 14, Vinod K. Paul, a NITI Aayog member who heads the panel on vaccination strategy, contradicted this. He told Reuters in an interview that the two vaccine candidates that the DCGI had approved would be treated equally. He said: “No vaccine is a backup to the other. Both vaccines are equally important, both vaccines are hugely immunogenic.” He added that there was no choice to the individual at this point of time as India was currently ramping up production of the vaccines.

If the two vaccines are being treated equally, why did the SEC and the DCGI use quite different language when announcing the approvals? Why did the two approvals come with different conditions, particularly the ‘clinical trial mode’ for Bharat Biotech’s Covaxin? As pointed out in an earlier article (Frontline, January 29), the convoluted statement by the two regulatory bodies said that permission for Covaxin had been granted “for restricted use in emergency situation in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains.”

Vaccine efficacy

Samiran Panda, an ICMR scientist, told The Wire Science that the ‘clinical trial mode’ administration would not have a comparator arm. A proper clinical trial has a cohort group that would be given a placebo with which the performance of the vaccine in the other arm of the trial, in which the participants are administered the vaccine, would be compared. But, strangely, he also stated that such a trial would not be registered with the CTRI. However, the participants, he said, would be briefed and given fact sheets about Covaxin so that they can opt out from taking it.

This means that beneficiaries receiving Covaxin in the first phase of the drive would be registered as participants in this unregistered single-arm trial for tracking vaccine efficacy. But how do you measure its true efficacy as this is not a clinical trial? As was pointed out in the earlier article, this ‘clinical trial mode’ is without blinding, without randomisation and without the placebo arm.

Also, who would constitute the Data and Safety Monitoring Board (DSMB) to authenticate the efficacy so determined if it is not a registered trial? Also, what Panda did not say, and which has subsequently been reported, is that those from the priority groups who get Covaxin would also be required to sign a consent form, just like in a clinical trial. So, as regards Covaxin, is it a vaccination drive in the garb of a pseudo Phase 3 trial or a pseudo Phase-3 trial in the garb of a regular vaccination drive?

This is not clear, because on the one hand the priority groups of HCWs and FLWs are being told that they are being lined up for vaccination because it is imperative that they should be protected against SARS-CoV-2 infection so that they do not get infected while attending to COVID patients. On the other hand, while they will get a vaccine, it may not be the vaccine of their choice. If they are lined up for Covaxin, whose efficacy is not demonstrated, and this vaccination drive is actually being used as a vehicle for testing its efficacy, it is their bad luck. Either they take it or opt out.

Also read: Hope as Covid vaccination drive begins

As Satyajit Rath said in the Newsclick discussion: “What they are being offered is a vaccine. If they are given Covaxin, they do not have the option of saying ‘I don’t want this, I want that.’ What appears to be happening is that either you take the vaccine that is being given to you or you don’t get a vaccine. That appears to be implicit coercion and a violation of freedom of choice.”

Also, which is the agency that is conducting this pseudo trial—the ICMR or Bharat Biotech? Rath said: “The vaccine is being purchased by the government and implemented. This means that the government is responsible for its administration. Yet, consent forms being required from these individuals who are being given Covaxin identify Bharat Biotech as the agency involved and responsible, particularly for treatment of adverse [side] effects, and so on. So, the entire landscape of Covaxin administration is a regulatory and public relations mess.”

Operationally, notwithstanding the statement by Paul that the two vaccines would be treated at par, it would seem that the government health officials are themselves unsure about Covaxin’s ability to offer protection, which is important from the perspective of the priority group of HCWs. Why then the differentiation in the supply of the two vaccines to the States and Union Territories, especially when the Health Secretary had said that all the 16.5 million doses would be procured by January 14?

Also, the distribution of doses to the 12 States that have been identified to get both vaccines (Table 1) cannot be explained. If the numbers of doses of the two vaccines procured are in the ratio of 2:1, it stands to reason that the distribution of the vaccines to these 12 States should also reflect that. But, as the table shows, it does not.

In fact, Adar Poonawala, CEO of SII, had stated that the company was ready with 100 million doses and Krishna Ella had said during his January 4 press conference that Bharat Biotech was ready with 50 million doses. Clearly, there were enough doses of both vaccines to supply to all the States and Union Territories and give the freedom of choice to the beneficiary. So, why this highly skewed distribution of only about 0.24 million doses of Covaxin? And what is the rationale for the uniform figure of 20,000 doses to 11 States?

According to a Health Ministry release of January 15, there are 3,006 vaccination session sites identified across all States and Union Territories and a target of 100 beneficiaries a day at every site had been set (about 0.3 million vaccines a day).

Also read: Will antibodies be able to protect us from the vaccine

This implies that the aim is to achieve a target of 30 million in about 100 days. However, the number would actually be less than 0.3 million a day even if all the sessions meet their daily target of 100 because individual States have chosen only 3-4 days of the week for the vaccination campaign so that other health services do not get unduly disrupted.

Even so, the initial pace until January 21 was quite tardy, with the number of people receiving the first dose of the vaccine through a total of 18,159 site sessions touching 9,99,065, which is only about 55 per cent of the targeted number of about 1.8 million in the six days since the drive began on January 16. (Two shots of both the vaccines are to be given, with the second dose to be given after a gap of 28 days.)

Messy drive

The possible reasons for this slow progress could be that either the promised doses of the vaccines had not been delivered yet to the vaccination sites or that the sites have fallen way below their daily target of 100. But more importantly, there have also been reports of vaccine hesitancy among the HCWs because of the uncertainty about the protection they would get after vaccination.

Satyajit Rath said: “The signals coming out about Covaxin are so complicated and without any direction as to create almost legitimate vaccine anxieties. I am saying that despite my concern that we may be feeding vaccine anxieties.”

Also, the digital platform CoWIN application created for uploading data on the ongoing campaign appears to have developed glitches, preventing speedy uploading of relevant data. CoWIN is an app meant to record data about vaccine beneficiaries that would enable the campaign administrators to keep track of whether the vaccine shots are being given to the priority cohort groups and also enable monitoring their post-vaccination status, particularly adverse events, if any. There have been accuracy issues. According to media reports, only three dry runs of the platform were done before scaling it up to all the vaccination sites in the country.

So, from all perspectives, the vaccine campaign appears to be messy. On the one hand, the government gets its hand-picked medical specialists to issue statements saying that the vaccines are efficacious even as there is absolutely no evidence—even in the form of interim data—to support the statements. Health officials are talking in different languages which even specialist HCWs, let alone non-specialists, are not able to understand.

Also read: The race for the Covid-19 vaccine

On the ground, people in the priority groups receiving Covaxin are under the impression that they are being vaccinated for protection while at the same time they are being told that the vaccine is being administered in ‘clinical trial mode’ for testing the vaccine’s efficacy.

Above all, the government does not seem to have got its act together in terms of effective communication to vaccine recipients, vaccine delivery and conduct of the campaign, resulting in vaccine hesitancy and low turnouts. Yet, it would seem that the government is going all out in its bid to get the campaign going before Republic Day so that a chest-thumping proclamation can be made to the nation.