News

First published in NewsGP

With ATAGI flagging that third doses and booster shots could soon be used to further protect against COVID, newsGP assesses preliminary results from Moderna and Pfizer’s ongoing clinical trials.

Questions regarding vaccine-induced immunity and booster shots have become particularly pertinent following the emergence of new variants of concern.
 
Reports from overseas indicate there is some reduction in long-term protection against symptomatic disease caused by the Delta variant, particularly among older cohorts.
 
These real-world experiences are also being increasingly supported by new studies, such as a recently published interim analysis of Moderna’s vaccine, which reports that the neutralising antibody response for variants such as Beta, Gamma and Delta can be so low that they are undetectable.
 
And while existing COVID strains are already proving challenging to contain, epidemiologists have predicted it is only a matter of time before yet another variant of concern emerges that further limits the efficacy of currently available vaccines.
 
But there is good news.
 
Professor Dale Godfrey, Immunology Theme Leader at the Doherty Institute, says the mRNA platform utilised by vaccine developers like Pfizer and Moderna should make adapting vaccines to particular variants a relatively simple process.
 
‘For these mRNA vaccines like Moderna and Pfizer, it’s really just a matter of changing the sequence to make the sequence align with the variants,’ he told newsGP.
 
‘Remembering these are just spike vaccines – not the whole virus – so they really just have to focus on the variations in the amino acid sequence of the spike of the variant, and then they set up an mRNA vaccine that will encode for those differences.
 
‘So the vaccines are made in almost an identical way, but just with a slightly different sequence that correlates with the variant.’
 
Likewise, adapting an adenovirus vaccine like AstraZeneca to respond to new variants is also possible – if perhaps slightly more complicated.
 
‘AstraZeneca is still a sequence; you have to re-engineer the genetic sequence for the spike that goes into the adenovirus vaccine vector,’ he said.
 
‘It may be a bit more complicated because you’ve got to incorporate it into the virus, but it’s not going to be dramatically different from the original AstraZeneca vaccine.’
 
Moderna, which arrived in Australia last week, and will likely be made available to GPs in the new year as part of a slated booster program, is already well advanced in its development of an updated candidate.
 
As part of an ongoing clinical trial, 80 people who had received two Moderna doses six months earlier were given a single booster dose of either the original vaccine (mRNA–1273) or one of two variant-modified doses: mRNA-1273.351 or mRNA-1273.211 – the latter being a mix of mRNA-1273 and mRNA1273.351.
 
The analysis found that all three were safe and well-tolerated, and neutralising antibodies increased – including against variants such as Delta – to levels that were either equivalent or superior to those generated after the second dose.
 
Professor Godfrey said the research is significant in that it not only shows a restoration of the immune response against COVID-19, but an enhancement.
 
‘The boost is doing more than just restoring it to where it was after the second injection; the boost is now taking it higher still,’ he said. ‘So that’s really reassuring.’
 
Research into Pfizer’s original mRNA vaccine as a booster has also been promising.
 
As part of a phase 3 clinical trial, 306 participants were administered a third dose of its original candidate between 4.8–8 months after receiving their second dose. The findings showed the booster elicited neutralising antibodies higher than after the second dose.
 
Though the findings are positive, Professor Godfrey says they are not entirely surprising, given that people receiving a booster shot are starting with a primed immune system.
 
‘This is why you need a prime and a boost to begin with,’ he said.
 
‘The first time you might only have a few hundred to a few thousand cells that are specific for the target antigen. After you prime, that number will increase dramatically and the next time you hit them with the same vaccine, you should have enough specific cells to give you a strong immune response.
 
‘How long that immunity lasts can vary a lot between vaccines, and in the case of Moderna and Pfizer at least, it looks like it does start to wane after about six months.’
 
However, even though antibodies have been shown to wane, that does not mean everyone will need a booster shot to protect them from severe disease.
 
‘That’s the important point here,’ Professor Godfrey said.
 
‘You need less antibody to protect against severe disease because … if you get infected and you’re vaccinated, your immune system will start cranking up again and it’s like being vaccinated again, if you like, except you’re doing it with the actual virus.
 
‘So you’ve got a head start over someone who wasn’t vaccinated.’
 
But while some vaccine experts have questioned whether there is enough evidence to support widescale booster programs, governments in Israel and the United States have moved ahead with efforts to administer third doses to their most vulnerable populations.
 
In response to these programs, the World Health Organization has warned about the need to firstly prioritise people in developing countries, ensuring everyone has the chance to receive at least one dose before third doses are administered.
 
Booster shots are also looking to be likely in Australia.
 
Just last week, the Australian Technical Advisory Group on Immunisation (ATAGI) issued a statement saying that it is considering the need for a third dose and anticipates ‘a relatively small cohort of individuals, such as those with severely immunocompromising conditions’ will be eligible, with official advice expected in the next few weeks.
 
Professor Godfrey says the considerations are multifaceted, and that it’s ultimately about assessing the evidence and finding the right balance.
 
‘There are certain people you really want to make sure have strong immunity, such as healthcare workers, and the booster is probably the best way to ensure that,’ he said.
 
‘But that doesn’t necessarily mean that the entire population needs booster shots now or within six months.
 
‘We’re really just learning now how durable the immune responses are, what the consequences are when your antibody levels drop down, how vulnerable you are to severe disease against Delta or whatever other variants might be emerging.
 
‘All these things are now questions that need to be worked out.’