Why India’s vaccination drive moves in fits and starts

Lakshmy Ramakrishnan

doi:10.1038/nindia.2021.91 Published online 24 June 2021

India launched the world's largest immunisation drive in January 2021.

© S. Priyadarshini

India launched its COVID-19 vaccination campaign on 16 January 2021, and by early February, 60 lakh people were inoculated. 

The country saw a glimmer of hope as the government announced vaccine candidates and rolled out a handful approved for emergency-use in India. But that hope did not last long – from being a self-reliant vaccine producer and a global vaccine hub, India slipped into being the centre of a massive and lethal COVID-19 battleground with a faltering vaccination strategy.

The surge is attributed to viral mutants, in particular Delta, the presence of asymptomatic cases, and super-spreading events, according to preliminary studies by the National Institute of Virology. 

These occurrences are thought to be responsible for increased transmission rates, increased disease severity, and increased number of hospitalisations and deaths. India reached a daily case count of over 3 lakh in April 2021, further devastating an overburdened healthcare system. The country was caught off guard by this ferocious new wave of Covid-19 infections.

Immunising 70% of a country of almost 1.3 billion people was never going to be a walk in the park. But the tortuous route that the vaccination drive took slowed it to a crawl. By mid-April, the government announced the third phase, which included individuals above the age of 18, a mammoth task that has thus far failed to gather momentum.

By June 2021, barely 50 million people were fully vaccinated in India, representing less than 5% of the population.

Weak estimates, limited capacity

In April and May, inability to meet the demand of those waiting to receive their second dose and those included in the third phase (18-44 year olds), marked the shortcomings in the vaccination drive.

Disruption in the supply chain goes back to the lack of proper estimates for vaccines, a piecemeal procurement strategy, and unregulated pricing. Currently, only two private manufacturers supply India’s vaccines. An obvious way to boost supply would have been to include more companies in the manufacturing ring. Though a few public-sector undertakings are capable of producing vaccines, some do not possess valid manufacturing licenses as their undertakings were not in accordance with good manufacturing practice (GMP) guidelines. 

It wasn’t till after five months of vaccine shortages that government approved three PSUs—Haffkine Biopharmaceutical Corporation,  Indian Immunologicals, and Bharat Immunologicals and Biologicals—to manufacture the approved vaccines.

The Indian government was also criticised for its vaccine diplomacy programme, Vaccine Maitri, launched at the same time as its domestic immunisation drive. While other nations planned their own immunisation schedules, India followed the path of ‘non nobis, sed omnibus’, which loosely translates as ‘not for us, but for everyone’. This attempt at goodwill diplomacy failed as India rapidly became a vaccine importer.

Three vaccine candidates have been approved for emergency-use in India. These are Oxford-AstraZeneca’s adenoviral vector vaccine (Covishield), manufactured by Serum Institute of India and AstraZeneca, India’s indigenous vaccine by Bharat Biotech, Covaxin, and Russia’s Gamaleya Research Institute’s Sputnik V,.

Bharat Biotech is seeking approval from WHO to include Covaxin in its emergency- use list of vaccines. Pfizer-BioNtech has produced an mRNA-based vaccine (Comirnaty®), not yet available in India. Negotiations between Pfizer and the Indian government are underway regarding Pfizer’s demand for an indemnity clause. Other overseas vaccine makers, including Moderna and Johnson & Johnson, are expected to roll out single-dose vaccines by 2022.    

Dose sparing, partial immunity?

These vaccines have a double-dose strategy. A single dose may be insufficient to elicit effective immune response. Booster shots, 3 to 6 weeks after the initial vaccination, ensure that immune response is complete and imparts long-term protection. Government of India has modified its immunisation schedule by increasing the dose interval from 6-8 weeks to 12-16 weeks for Covishield. This followed a recommendation  by the government’s COVID Working Group on the basis of recent research findings.

A study showed that at a dosing interval of 12 weeks, efficacy of the Oxford-AstraZeneca vaccine was 81%, while the earlier recommended 6-week interval reported an efficacy of 55%. Another study reported that a single ‘priming’ dose brought about immunity that lasted upto 90 days post-vaccination, indicating that a booster would be required after 3 months.

In addition, a study by Pfizer-BioNtech on individuals above age 80 observed that the level of neutralising antibodies was more than 3.5 times in vaccinated individuals who had a gap of 12-weeks  between doses, compared to those who had a gap of three weeks. Accordingly, the UK delayed the second dose of vaccine (Oxford-AstraZeneca or Pfizer-BioNtech) to 12 weeks.

The aim of this dose-sparing strategy was to vaccinate the maximum number of eligible people with the first dose and avoid vaccine shortage. Sceptics say this may generate a population only partially immune and could serve as an ideal environment for viral mutations to occur that confer selective advantages, such as increased transmissibility or the ability to evade immune responses.

Adverse reaction, vaccine design

Reports of blood clots in individuals inoculated with the Oxford-AstraZeneca vaccine reiterated how safety concerns are of utmost importance. Vaccine-induced autoimmunity occurs as a result of immune cross-reactivity. It refers to a series of adverse reactions as a result of molecular interactions between the vaccinated host and the vaccine components.

It is likely due to the presence of significant similarity between host proteins and viral components of the vaccine. This immune cross-reactivity leads to a series of reactions where the immune system’s response towards the antigen may get directed towards host proteins as well, triggering autoimmunity within the vaccinated host.

Recent reports of thrombotic events in individuals vaccinated with Covishield  suggest that vaccination may trigger the production of auto-antibody platelet-factor 4 (PF4), through this mechanism. The adverse thrombotic reactions are referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

This suggests that vaccine design needs to be modified to eliminate chances of cross-reactivity. The Ontario Covid-19 Science Advisory Table advices clinicians to be on the watch for symptoms of VIPIT, including persistent headaches, double vision, seizures, shortness of breath, swelling and redness of limbs, which arise five to 20 days post-vaccination.

Confirmatory diagnosis is carried out through blood tests that detect autoantibody PF4 and D-dimer, indicative of thrombotic events. Imaging studies are also used. Treatment of VIPIT is intravenous administration of immunoglobulin.

Given the rarity of these adverse reactions and that the vaccine was found to be safe and efficacious in clinical trials, mass vaccination strategies were cleared but one must err on the side of caution. There is an urgency to understand the clinical risks associated with the potential of vaccine-induced autoimmune conditions.

Low transparency, high hesitancy

India’s vaccine shortage is twinned by vaccine hesitancy. This should not come as a surprise considering the abundance of information on vaccine efficacy, availability, pricing, and dosing strategies disseminated through mass media.

Doubts over Covaxin’s safety and quality were raised when Brazil halted its order of the vaccine over concerns raised by its health agency about Bharat Biotech’s compliance to GMP standards. This was exacerbated by the Drug Controller General of India’s approval of Covaxin’s use in India even prior to completion of phase III trials.

While the accelerated approval to Covaxin has been attributed to the favourable completion of phase I/II trials, failure to publish phase III trial data aroused suspicion, particularly as it pertained to vaccine safety. Bharat Biotech have submitted their Phase III clinical trial data to India’s regulators, who are expected to make it public by July.

To counter the doubt over safety, it is important that the Indian government publish positive reinforcement of vaccine safety profiles, which must include publication of clinical trial data. This alone will create confidence within the population, particularly since one aim of the vaccination campaign is to arrive at herd immunity.