Second boosters: What the studies tell us about the fourth COVID-19 jab

Zhuang Pinghui, South China Morning Post

Posted at May 16 2022 01:56 PM

People get their second COVID-19 booster shot at a vaccination site inside Robinson’s Place Manila on April 26, 2022. The health department has started to roll out second booster shots for the immunocompromised A1 and A2, consisting of health workers and senior citizens, as additional protection against the fear of another surge. George Calvelo, ABS-CBN News
People get their second COVID-19 booster shot at a vaccination site inside Robinson’s Place Manila on April 26, 2022. The health department has started to roll out second booster shots for the immunocompromised A1 and A2, consisting of health workers and senior citizens, as additional protection against the fear of another surge. George Calvelo, ABS-CBN News

With Covid-19 cases surging again, many countries have rolled out fourth doses of the vaccines.

But most of these second booster programmes are just for vulnerable groups like the elderly and the immunocompromised as questions remain over how lasting the immunity is, and if a second jab will benefit the wider population.

There have been some studies done on the effectiveness of a fourth dose but more research is needed. Here is what the data tells us so far.

Most of the data so far comes from Israel - the first country to start giving fourth jabs to people aged 60 and over, as well as high-risk groups such as the immunosuppressed and their carers.

One study compared the effectiveness of third and fourth doses of the Pfizer mRNA shot. To do this, it looked at the health records of more than 182,000 people aged 60 and over from January 3 to February 18 - when the Omicron variant was dominant.

In findings published last month in the New England Journal of Medicine, the fourth dose was found to have provided significantly more protection against severe disease, hospitalisation and death for at least a month.

Seven to 30 days after the fourth jab was given - compared to someone given a third shot - the relative effectiveness was 45 per cent against infection, 55 per cent against symptomatic disease, 68 per cent against hospitalisation, 62 per cent against severe disease and 74 per cent against death.

An earlier study published in the same journal looked at the incidence of breakthrough infections and severe illness among people aged 60 and over. The study involved more than 1.2 million people in Israel and found those who had received three doses were 3.5 times more likely to develop severe illness than those who had been given four jabs during the Omicron wave.

It found there were 177 infections per 100,000 people who had received a fourth dose. That compared to 361 per 100,000 in the group that had three jabs.

A small trial of 166 people in the United Kingdom, meanwhile, has found that a full dose of Pfizer or a half dose of Moderna given as a fourth shot - about seven months after the third - provides an immunity boost for the elderly.

There was a 1.6-fold increase in antibodies among those who received the Pfizer vaccine, and a more than twofold increase for those given Moderna compared with the peak of the antibodies, according to findings published in The Lancet last week. The level of T-cells also increased after a fourth dose of both vaccines, suggesting more lasting immunity. The UK began rolling out fourth doses for people over 75 in April.

Some serious adverse events were reported in the UK trial but were considered to be unrelated to the vaccine. The most reported side effect was injection-site pain, which was mostly mild or moderate. Fatigue, headache, malaise and muscle ache were also commonly reported.

"These data show that a fourth dose of Covid-19 mRNA vaccines is well tolerated," the researchers wrote.

The study in Israel involving over 1.2 million people showed protection from the fourth dose against severe illness did not wane during the six weeks after the jab. It found that protection against infection waned after four weeks, and concluded that more follow-up research was needed.

The UK trial found that a fourth mRNA dose given more than six months after a third jab provided a significant increase in anti-spike protein antibody titres, though the researchers said this would probably "wane rapidly", as has been seen after the third dose.

The vaccines also trigger production of other immune defences, including T-cells, which offer more lasting protection.

While a second booster is considered reasonable for at-risk groups, its benefit for the wider population is less meaningful, according to the limited available data.

In an open-label, non-randomised clinical study in Israel, 272 healthcare workers were given a fourth dose of either the Pfizer or Moderna mRNA vaccines. Double the number of healthcare workers of matching ages and without the fourth jab made up the control group.

The study found a second booster induced antibodies that neutralised Omicron and other variants and the difference between the two vaccines was not significant. But there was no substantial difference from a fourth dose in terms of humoral immune response or levels of Omicron-specific neutralising antibodies compared to the third dose. That suggested the maximum ability to provoke an immune response is achieved after three doses, according to the researchers.

"A fourth vaccination of healthy young healthcare workers may have only marginal benefits," they wrote.

Most studies on fourth doses have looked at mRNA vaccines. But in China, inactivated vaccines are mostly used. The country has yet to approve a fourth dose.

A non peer-reviewed study by Sun Yat-sen University in Guangzhou, published in February, found that levels of neutralising antibodies did not increase with a fourth dose, and even dropped. The study suggested that immune response could not be boosted endlessly and there would be a "turning point" after repeated vaccination.

Last week, Soumya Swaminathan, chief scientist at the World Health Organization, said the WHO's position was that countries could decide to give fourth doses for some groups but not to the whole adult population.

"It is a question of prioritising first to make sure that people are protected with the primary course and then giving a further layer of protection to those who might need that addition," Swaminathan said.

She said there were only about seven studies that had looked at fourth doses so far, and the data suggested they gave an antibody boost but it was not long-lasting.

"These studies have not followed these people up for longer, so we don't know how long-lived that protection is ... we don't have enough data to recommend that broadly at this point," she said.

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