Mind the gap: How dose interval progressed in India and what’s the ideal gap between two Covishield shots?

The Oxford-AstraZeneca vaccine or AZD1222 vaccine (in India, Covishield) has never been out of the news. Originally planned to be a single dose, it ended up as a two-dose vaccine.

In clinical trials, two shots were supposed to be administered with a gap of four weeks. However, participants received vaccines at variable intervals of four to 12 weeks.

When clinical trial data from the United Kingdom, South Africa and Brazil was analysed, the vaccine efficacy was found to be 55 percent if two doses were administered at an interval of less than six weeks and around 80 percent if administered with a 12-week gap.

However, when the findings from the phase 3 clinical trial of the Oxford-AstraZeneca vaccine in the United States of America became available in March 2021, the efficacy at a four-week interval was found to be 76 percent.

Vaccine experts’ generic conclusion is that the longer the gap, the higher the efficacy of the vaccine. The United Kingdom chose to implement a 12-week gap for two shots of the vaccine. Many countries, such as Canada, Spain, Thailand and Bangladesh, had followed (and continue to follow for specific groups) either a 12-week interval or an even longer one.

How dose interval has progressed in India

India licensed the vaccine on 3 January, 2021. However, it adopted a gap of four-six weeks for two shots. This was done as the bridging study on Covishield in India was for a four-week interval.

Apparently, the operational consideration was also factored in.

The other vaccine introduced in the COVID-19 vaccination drive in India, Covaxin, also had a four-six-week interval. Therefore, keeping that dose interval would result in avoiding any confusion and ensure operational simplicity.

A few weeks later, data from the Oxford-AstraZeneca vaccine study was published in a peer-reviewed journal, concluded that a longer gap works better. In the second week of March, a World Health Organisation expert group also recommended an interval of 4 to 12 weeks for this vaccine. India extended the dose interval to six to eight weeks on 23 March, 2021.

April 2021 onwards, there was a shortage of vaccine supply in India, which was further aggravated with the opening up of the exercise to the 18 to 44 age group. This happened along with additional scientific evidence that a longer gap worked better. Much of the surge in the UK was tackled by following this schedule of two shots 12 weeks apart.

The National Technical Advisory Group on Immunisation (NTAGI) in India recommended increasing the gap between two shots of Covishield to 12 to 16 weeks. The country was in the middle of a ferocious second wave and one of the key considerations was administering at least one dose to as many people as possible.

Why fixed-dose intervals for other vaccines?

Oxford-AstraZeneca /Covishield /AZD1222 is a viral-vectored vaccine. This is the first time that a vaccine for human use has been developed on this platform (Sputnik and Novavax are also on the same platform). In this technique, a part of the genetic sequence of the antigenic portion of SARS-CoV-2 (the section which activates the immune system without causing the disease) is inserted into non-replicable Chimpanzee adenovirus (which serves as a vector).

Once such a vaccine is administered to a human, the adenovirus enters into the cells, multiples and makes copies of the antigenic portion of SARS-CoV-2. More copies of the antigenic portion are created in human bodies to generate an immune response, which is believed to provide protection with a single dose, though at a lower level and for a limited duration.

This is very different from inactivated or killed vaccines such as Covaxin, where there is no such replication of antigenic material in the human body. Therefore, in Covaxin, the first dose merely primes the immune system, and to kick off any benefits, the second shot should be administered in a timely manner of 4 to 6 weeks to boost the immune system.

However, in Oxford-AstraZeneca, the evidence shows that a single dose can provide some protection for some duration.

What has changed now?

India changed the Covishield dose interval to 12 to 16 weeks on 13 May, 2021. A few days after that, a study from Public Health England reported that a single dose of Oxford-AstraZeneca vaccine has 33 percent effectiveness against the symptomatic disease, not 65 percent to 85 percent, which was estimated earlier.

Thereafter, the UK reduced the gap for people older than 50 years to eight weeks from 12. However, the recommended gap of 12 weeks continued for those younger than 50 years.

In early June, studies from India noted that the second wave of the pandemic was fuelled by a new variant later named Delta (B.1.617.2). This variant is considered 50 to 70 percent more transmissible in comparison to the Alpha variant, has potential to cause breakthrough infection (people with prior vaccination can get infected) and immune escape (people with immunity due to prior natural infection can also get an infection).

Public Health England reported that the Delta variant can possibly cause more serious disease (something which has not yet been reported in India).

A few studies on neutralising antibodies against various vaccines (Pfizer-BioNTech, Covaxin and Covishield) have also reported that the Delta variant results in a three to six-fold reduction in neutralising antibodies. However, all of these vaccines have been found to work against the variants. But there are concerns that the effectiveness of these vaccines may not be similar to the reaction against the Alpha variant or original ancestral virus first reported from Wuhan on 31 December, 2019.

There have been many developments in the past 10 days. A new mutation in the Delta variant has been reported from at least 10 countries including India. This new variant with additional mutation is being termed as Delta Plus. Though there is not much information available, initial reports indicate that the Delta Plus variant has some resistance to Monoclonal antibody combination therapy being used as investigational therapy.

The most recent concern about two-dose intervals between the Oxford/Astra-Zeneca vaccine has emerged from the latest PHE study which has reported that a single dose of the vaccine has a 71 percent effectiveness against severe disease and hospitalisation. This goes up to 92 percent after two doses. Based on this evidence, the UK has extended the eight-week gap between two shots to those 40 years and older (earlier, it was 50 years).

What next for India?

Vaccination schedules are always informed by scientific evidence. However, operational reasons are also factored in while deciding the immunisation timetable. That is the reason countries follow various schedules. At present, Thailand, Spain and Canada and Bangladesh follow a 12-week or longer gap between two doses.

However, with the Delta variant being the most common in India, there is a renewed discussion to revise the interval to a shorter one and focus on achieving full immunisation coverage for a smaller proportion of the population than a single dose for a larger section.

That is not an easy choice to make.

Let’s see what technical experts on immunisation, who advise the Government of India, decide.

A common person, however, needs to remember that there is no cause to worry about the 12-week gap. Every setting has a different approach to implement a programme. All countries consider local evidence to arrive at any decision. The UK has fought the pandemic with two doses administered at a gap of 12 weeks. They are changing the schedule only when nearly 90 percent of their population has received at least one shot.

Vaccine dose interval is always a dynamic process, which can change based on available evidence. Till NTAGI in India reviews all the evidence and suggests an alternate course, an interval of 12 to 16 weeks between two doses of Covishield vaccine is what all of us should follow.

The important thing is that everyone who is eligible for COVID-19 vaccination should get their shots as per the recommended schedule.

The author is a public policy and health systems expert. He is the co-author of Till We Win: India’s Fight Against The COVID-19 Pandemic. He tweets at @DrLahariya. Views expressed are personal