The NIH’s proposal to use available data to investigate a half dose of Moderna’s authorised COVID-19 vaccine, mRNA-1273, for younger people will be onerous to execute, experts said. While it is theoretically sound to consider a smaller dose for some, experts took issue with the multiple assumptions that have to be made to extrapolate Phase III results from the authorised 100μg dose to available Phase IIa 50μg immunogenicity data, they added.

In the past few weeks, governments and commentators have argued for decreasing doses or extending the gap between two-dose vaccines as tactics to extend the available vaccine supply. The FDA did not dismiss such suggestions entirely but noted more data is needed for changes to transpire. In an interview with the New York Times (NYT; 5 January), NIH Vaccine Research Centre director Dr John Mascola suggested that to assess the value of using the 50μg dose of mRNA-1273, they would use Phase III results to correlate 100μg immunogenicity to protection and then either compare that correlate data to existing Phase IIa 50μg immunogenicity results, or a new Phase II trial would be run.

Experts this news service interviewed said it is logical that a lower dose may be ideal for younger people, considering they have stronger immune systems and are less likely to have severe disease, but collecting evidence to prove so will be challenging. To start, correlating immunogenicity results with protection will be tough due to the limitations of the available data. This is on top of lingering questions of whether neutralising antibody titers are an appropriate surrogate marker for protection.

Even if correlate data is established from Moderna’s Phase III testing the 100μg dose, comparing those results to Phase IIa 50μg immunogenicity data comes with the assumption that the vaccines given in both trials were the same, which is unclear, experts said. Additionally, Phase IIa 50μg data, while encouraging, only delivered an efficacy signal, some added. While experts said staging new trials would provide the most clinically reliable data, they noted trial implementation hurdles and results may be too late to make a difference.

Immunogenicity-protection correlate data may be elusive

In the NYT article, Mascola said that to provide the FDA with data to support an mRNA-1273 dosing change, the first step is to identify what immunogenicity levels correspond to protection in the Phase III trial.

The rationale behind using Phase III 100μg dose data to find the correlation between immunogenicity and protection is to do away with another large-scale Phase III trial looking into protection for the 50μg dose, explained Dr Paul Goepfert, director, Alabama Vaccine Research Clinic, University of Alabama, Birmingham. Assuming that 100μg correlate data is identified, and Phase III 100μg and Phase IIa 50μg immunogenicity data are comparable, then it could be assumed that both doses could offer the same protection, added Professor Paul Heath, director, Vaccine Institute, St George’s, University of London, UK.

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However, correlate data will be challenging to identify given the fact that Moderna’s vaccine demonstrated high Phase III efficacy in preventing Covid-19 illness, said Dr Stephen Thomas, chief, Infectious Disease Division, Upstate Medical University, Syracuse, New York. There are four sets of Phase III immunogenicity data needed to pinpoint the correlation between immunogenicity and protection: vaccine-arm immunogenicity results in people who have not been infected and those who have been infected as well as placebo-arm data on people who have and have not been infected, explained Heath.

However, because Moderna reported 94.1% efficacy, there are not enough people in the vaccine arm who have been infected to provide robust immunogenicity data, noted Thomas, a Phase III Pfizer/BioNTech Comirnaty (BNT162b2) investigator. mRNA-1273’s efficacy is based on 195 symptomatic events in the placebo group and 11 in the vaccine group (Baden L. et al., N Engl J Med. 2020 Dec 30;NEJMoa2035389). Comirnaty—also an mRNA vaccine—is the other vaccine with an FDA Emergency Use Authorisation (EUA) and has 95% efficacy in preventing symptomatic Covid-19 (Polack F. et al., N Engl J Med. 2020 Dec 31;383(27):2603-2615).

Perhaps a better shot at identifying correlate data is with the University of Oxford/AstraZeneca’sAZD1222, as this vaccine has more infected people in the vaccine arm, said Heath, a UK-based investigator in the Phase II/III AZD1222 study and Novavax’s Phase III NVX-CoV2373 trial. Based on a pooled analysis of Phase II/III trials in the UK and Brazil, AZD1222 has a 62.1% efficacy in preventing symptomatic disease based on 27 versus 71 infection events in the vaccine and placebo groups, respectively (Voysey M. et al., Lancet. 2021 Jan 9;397(10269):99-111).

But the various Covid-19 vaccine trials have different definitions of an event, making extrapolations challenging, a Phase II/III AZD1222 investigator noted.  In the Moderna trial, Covid-19 tests were conducted in those who developed at least two symptoms from one list or one symptom from another list, while the AstraZeneca trials only require one symptom. Having uniform correlate data for Covid-19 vaccines is challenging as it would require trial samples from around the world to be sent to a centralised laboratory for analysis, the AZD1222 investigator noted.

Additionally, it is still unclear if neutralising antibody changes is an appropriate surrogate marker for protection, Thomas said. “We don’t know what we need,” Heath added. Perhaps cell-mediated immunity is a more relevant surrogate marker for protection, he noted. None of the Covid-19 vaccines have detailed cell-mediated immunity data from human trials, Goepfert said.

Supporting the idea that neutralising antibody titer changes could eventually be the definitive surrogate measure for protection is that people who have been infected with SARS-CoV-2 are protected from reinfection for six months, said Goepfert, a Johnson & Johnson Phase III JNJ-78436735 investigator. Neutralising antibodies are also used in influenza vaccine studies, and there seems to be a correlation between neutralising antibodies and protection in Covid-19 animal models, Heath added.

Potentially arguing against neutralising antibody as a surrogate for protection is that in the Moderna Phase IIa trial, antibodies peaked at day 43 after the second dose. But Goepfert says this decrease is not concerning, as such an immune response doesn’t stay at these levels long-term. What is relevant, though, is whether neutralising antibodies continue to decline, he added. But volunteers would have to be followed for months, if not years, to check if neutralising antibodies persist, added Dr Mark Rupp, chief, Division of Infectious Diseases, University of Nebraska Medical Centre, Omaha. It may be impossible to know the full answer to correlate data, Rupp said. On 18 January, the NYT reported that Moderna is offering a third shot to Phase I participants. This trial design addition is likely to be a consideration for all Covid-19 vaccines owing to the lack of data regarding efficacy durability, Heath added.

While convalescent plasma could be used to pinpoint if neutralising antibodies or cell-mediated immunity are most relevant for protection, there may be differences between immunity triggered by natural infection versus vaccines, Heath said. There is wide immunogenicity variance among naturally infected patients, which makes convalescent plasma also not ideal in establishing immunogenicity benchmarks for protection, Thomas added.

Data gaps present with Phase IIa 50μg data

Even if neutralising antibody levels or cell-mediated immunogenicity could be identified as a protection surrogate, experts cautioned against judging the protective efficacy of the mRNA-1273 50μg dose based on existing Phase IIa results. While Mascola declined this news service’s request to elaborate on the NIH’s potential strategy, the NYT article states that he said once Phase III immunogenicity-protection correlate data is identified, Phase III 100μg immunogenicity data could be compared with Phase IIa 50μg immunogenicity results. Moderna did not respond to a request for comment.

For data comparisons between the Phase III and IIa to be appropriate, there needs to be a guarantee that the same vaccine was used in both studies, Thomas said. Typically, Phase II results can lead to vaccine changes prior to Phase III to improve the risk-benefit profile, he explained. AstraZeneca’s studies were designed as Phase II/III trials to allow for Phase II immunogenicity data to help with a seamless transition to the Phase III stage, confirmed the AZD1222 investigator. Pfizer/BioNTech initially investigated four different vaccine configurations in Phase I/II before choosing one for Phase III.

Furthermore, while Phase IIa immunogenicity data is available, the sample size is too small, Heath said. In Moderna’s 600-volunteer Phase IIa studying immunogenicity of 50μg and 100μg doses, regardless of dose, a 20-fold increase in binding antibodies and a 50-fold increase in neutralising antibodies were observed, according to Moderna’s December presentation. Available Phase IIa data does not have statistical analysis between arms, nor differentiation between separated cohorts of volunteers ages 18–55 years and 56 years and over.

Another potential way to measure 50μg protection potential is by counting how many of the 200 Phase IIa volunteers who received this dose reached the Phase III 100μg immunogenicity benchmark. But experts did not want to discuss how to use Phase III correlate data against Phase IIa results via this methodology, considering too many assumptions must be made for such an analysis.

Staging new trials would be a better strategy, but execution obstacles persist, experts said. Data from a new Phase II immunogenicity study may be too late to answer pressing questions of the worthiness of the vaccine at half-dose, and a large-scale Phase III event-driven trial would be burdensome financially as well as on available healthcare resources, they said.

Reynald Castaneda is an 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.