Among the strategies being proposed to extend available Covid-19 vaccine supplies, delaying the second dose of an authorised two-dose vaccine is relatively more grounded in clinical data than reducing doses, investigators said. Nonetheless, they were sceptical if either approach would solve the sluggish start of vaccine distribution in the US and Europe.
Both regions have had to grapple with Covid-19 vaccine distribution teething issues, which is in stark contrast to the unprecedented quick pace of vaccine authorisations. While the UK advised booster shots can be given later than what was tested in registrational trials, the FDA and European Commission (EC) authorisations reflected the durations tested in Phase IIIs. However, just last week, the US CDC noted second shots may be given up to six weeks later.
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Investigators this news service interviewed noted there is more evidence supporting a delayed booster shot, with some trials administering the booster 12 weeks after the first. However, others noted, this may not apply to all vaccines, as some trials’ high compliance rate means they do not have efficacy data beyond three weeks after the primer shot.
To draw clinician and public buy-in for new vaccination schedules or dosing, new clinical trials may be needed, investigators said. Yet, starting trials now would be a financial and resource burden and may be too late to address the urgency of getting more people vaccinated, they said.
In fact, the challenge is less with vaccines being in short supply but rather with ensuring these supplies reach the public, investigators said. Changing vaccine schedules or doses is unlikely to solve these pressing distribution obstacles, they noted. Additionally, execution failures are more likely with a vaccine with two different doses, said Dr Paul Goepfert, director, Alabama Vaccine Research Clinic, University of Alabama, Birmingham. If there is limited supply, boosting manufacturing would be a better solution than changing vaccination protocols, he added.
Pfizer and BioNTech’s Comirnaty (BNT162b2) and Moderna’s mRNA-1273 have emergency use authorisation (EUA) in the US and UK, while the University of Oxford/AstraZeneca’s AZD1222 is only authorised in the UK.
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By GlobalDataAZD1222 has more data for wider vaccination window
On 21 January, this news service reported experts were sceptical of an NIH-suggested approach to gathering data to support mRNA-1273 at half dose for younger people. Phase III data that correlates 100μg immunogenicity and protection would be challenging to collect due to limitations of available results and lingering questions as to whether neutralising antibody levels is the right surrogate marker. In addition, the availability of a 50μg half dose could be a confounding factor for vaccine programs, since older people who need the full dose could be given half doses, Goepfert noted, adding vaccination campaigns aim for consistent dosing and schedules regardless of the vaccine receiver’s profile.
Between delaying the booster and reducing doses, the latter is harder to prove, said Professor Paul Heath, director, Vaccine Institute, St George’s, University of London, UK. In any Phase III Covid-19 vaccine trial, all volunteers receive the same dose, whereas there could be participants in the same trial who received the booster later than other participants, Heath explained. For example, in the Moderna Phase III trial, 93 people received the booster outside the 28-day window that the study set out to test. These volunteers were excluded from the final analysis (Baden L et al., N Engl J Med. 2020 Dec 30;NEJMoa2035389). mRNA-1273’s US and UK authorisations specify administration of the second dose 28 days after the first dose.
On 21 January, the CDC noted, while the booster should be administered as close to the recommended interval as possible, Comirnaty’s and mRNA-1273’s second shot may be given up to 42 days later. On 30 December, the UK’s MHRA said AZD1222’s doses can be administered 4–12 weeks apart, while Comirnaty’s booster dose may be given 3–12 weeks later.
The UK’s MHRA guidance to increase the dosing interval for AZD1222 and Comirnaty compared to how they were tested in registrational trials was made to ensure more people receive at least one dose of the vaccine, explained Heath, a UK-based investigator in the Phase II/III AZD1222 study and Novavax’s Phase III NVX-CoV2373 trial. A single dose could allow an individual’s immune system to have some degree of protection from severe disease, said Geert Leroux-Roels, professor emeritus, Faculty of Medicine & Health Science, Ghent University, Belgium.
However, the Phase III data showing Comirnaty’s efficacy with just one dose is based on only a handful of events, said Dr Stephen Thomas, a Phase III Comirnaty investigator and chief, Infectious Disease Division, Upstate Medical University, Syracuse, New York. In the interval between the two injections, the vaccine has an efficacy of 52%, while it has a 95% efficacy based on events counted seven days after the booster (Polack F et al., N Engl J Med. 2020 Dec 31;383(27):2603-2615). Delaying the Comirnaty or mRNA-1273 boosters is also not supported by robust data, noted Thomas, explaining there is high compliance rate for both Phase IIIs, so there is little data of the primer’s efficacy beyond 2–3 weeks. In a media statement (4 January), Pfizer/BioNTech said there is lack of trial data to support delaying the booster shot. Companies mentioned in this article and the University of Oxford did not respond to this news service’s comment request.
In contrast, there is data supporting a longer gap between AZD1222 doses, a Phase II/III AZD1222 investigator noted. In the Brazil AZD1222 trial, the second injection was administered up to 12 weeks later, with 61% of the 4,088 volunteers included in the first data analysis receiving the second dose with a six-week gap. In the UK-based trial, among volunteers who received standard AZD1222 doses, the median dosing interval was 69 days (Voysey M et al., Lancet, 2021 Jan 9; 397(10269):99-111). When AZD1222 was under investigation as a single dose, this news service reported June 2020 that a potential way to improve its efficacy data in animal models would be to administer a second dose after four months.
New trials help public buy-in but not solution to distribution woes
Changing doses or vaccination schedules with limited information risks losing public credibility, Thomas cautioned. None of these vaccines have full approval, and existing data, while still limited, has relatively robust results supporting specific doses and timelines, he noted.
Fresh trials investigating altered protocols may be the best option. To investigate half-dose mRNA-1273, for example, if there is Phase III immunogenicity-protection correlate data, estimating the 50μg dose’s protection efficacy based on existing Phase IIa immunogenicity data comes with too many assumptions, experts said. Instead, a new Phase II 50μg immunogenicity trial would be ideal to add to the evidence obtained from 200 volunteers in the Phase IIa trial, Heath said. At the very least, the trial would replicate the Phase IIa design to confirm results, he added.
A head-to-head noninferiority immunogenicity trial versus the 100μg dose might be enough to validate the 50μg dose, said Goepfert, a Johnson & Johnson Phase III JNJ-78436735 investigator. A superiority trial investigating the different doses may take at least six months, as it would likely be hard to tease out immunogenicity differences between the two arms, added Dr Mark Rupp, chief, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha.
Nevertheless, given the urgent need to address the Covid-19 pandemic with vaccines, staging yet another Phase II trial may mean it could be too late for its results to have real-world impact, the AZD1222 investigator noted.
However, Rupp said, a new Phase III trial investigating 50μg mRNA-1273 would be the best way to get definitive answers. Event-driven Phase III trials with a protection primary endpoint can be run now due to high US infection rates, Goepfert noted.
But a Phase III would be even more of a challenge, as it takes time and high financial investment, Thomas added. The existing Phase III mRNA-1273 trial is still ongoing, which means it could potentially be expanded to recruit around 1,000 more participants with two 50μg injections, he noted. Efficacy of a single dose of the mRNA vaccines could be investigated; all participants would receive two doses, but half of these volunteers’ second shots would be placebo, he added.
Nevertheless, experts were dubious about changing vaccination doses or schedules to solve the challenge of getting more people vaccinated. The reason why vaccination programs have yet to gather momentum is not due to strained supply but due to distribution hurdles, noted Thomas.
Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.
