by Reynald Castaneda in London.

Registrational trials for Covid-19 vaccines will have many operational obstacles, even though they agreed that they may only need to reach the lowest success bar of 50% protection over at least six months to be considered a success.

On 7 May, Moderna made several announcements, including that it was finalising the design of its Phase III, slated for the summer, and its share price that day peaked at 14%. While its mRNA vaccine candidate, mRNA-1273, is perceived to be the frontrunner, Inovio Pharmaceuticals also has summer plans for a Phase II/III trial of its DNA plasmid vaccine INO-4800, leading to a 5% bump on 28 April after the announcement.

On 9 April, a World Health Organization document noted two success benchmarks for vaccines. Preferably, the vaccine should have at least a 70% efficacy on a population basis with durability for at least a year for reactive use in an outbreak and/or protection for those with a high ongoing risk. The lower success bar is about 50% efficacy with at least a six-month durability.

The 50% success bar, while low, is acceptable, as it would likely be enough to ease the pressure on frontline healthcare resources but it may not be high enough to reach herd immunity. To achieve this lower bar, an estimated tens of thousands of participants would need to be enrolled, with a 25,000–30,000 volunteers for sufficient powering of a trial starting in the summer.

Such a large trial will result in multiple operational obstacles, as reduced community infection rates would blur efficacy and could prolong trial timelines. The multiple vaccine trials will also be competing for the same participants in regions where there is still community transmission. Additionally, for an infection rate reduction primary endpoint, rigorous testing is needed, but this is currently lacking overall.

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Another challenge for a Phase III of this magnitude is that no company has yet fully demonstrated that its vaccine is scalable, noted Wen-Hsiang Chen, PhD, director, quality control and analytical development, Texas Children’s Hospital Center for Vaccine Development, Houston. On 1 May, Moderna announced it had signed a 10-year strategic manufacturing collaboration with Lonza, with US manufacturing to start in July. They plan to coproduce 1 billion doses annually, assuming a 50µg dose administered twice, 28 days apart.

Interim data from the Phase I mRNA-1273 trial (NCT04283461), funded by the National Institute of Allergy and Infectious Diseases, was revealed 18 May, which shot the stock up almost 30% premarket; Phase II is expected to start imminently, with Moderna receiving FDA fast track designation on 12 May. While the mRNA vaccine candidate has a manufacturing edge, and its choice of the SARS-CoV-2’s spike protein as the antigen found expert support, a number of difficulties lie ahead to confirm protection, this news service reported on 16 April. Even if Moderna’s Phase II data reveals an increase in immunogenicity, Phase III data will carry the weight for Covid-19 vaccine approval, as it will put antibody titre data into context, several experts noted.

Moderna, which has a $29.7bn market cap, did not respond to a comment request.

Many hurdles to running a large-scale trial

Decreasing community infection rates due to lockdown measures could potentially challenge Phase III implementation, said Didier Betbeder, PhD, leader of the nanomedicine group, University of Lille, France. Another scenario is that there could come a time when enough of the general public has been infected to the point that there is herd immunity, added Paul Aebersold, an ex-FDAer and independent consultant on regulatory strategy.

A Phase III trial will likely require several thousands of participants, depending on the infection rate, said Dr Kathryn Edwards, professor of paediatrics, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee. During an earnings call on 9 May, Moderna Chief Medical Officer Tal Zaks said one element to the trial’s success is predicting the attack rate.

There are many assumptions on what the infection rate will be in the summer when Moderna’s expects to start its Phase III; one of these is an annualised 1.5% incidence rate, said Peter Gilbert, PhD, biostatistician, Fred Hutchinson Cancer Research Center, Seattle, Washington. At this rate, the Phase III trial would likely need 25,000–30,000 subjects, who would be followed for a year, added Gilbert, who oversees statistical analyses of international vaccine trials. This trial sise would ensure powering to investigate if the vaccine can provide 50–60% efficacy, defined as the percent reduction in disease acquisition rate, he noted.

If the incidence rate is lower than 1.5% by the summer, the trial would need to have a broad geographic footprint, Gilbert said. David Benkeser, PhD, assistant professor, biostatistics and bioinformatics, Rollins School of Public Health, Emory University, Druid Hills, Georgia, agreed, adding that there should be collaborations between vaccine trial management and experts in modelling disease transmission because these groups do not necessarily overlap.

There is the added complication of the different vaccine trials competing for participants in specific areas where the virus is still in the community, said Bernard Van der Zeijst, PhD, professor, Department of Medical Microbiology, Leiden University Medical Center, The Netherlands. At least 15 assets are in clinical trials and at least 100 in preclinical testing. Other companies in the vaccine development race include BioNTech , CanSino Biologics, Novavax and Sinovac Biotech. Reassuringly, recruitment at this magnitude would be helped by many people keen to contribute for the greater good, similar to the experience with anthrax vaccine research, said Edwards.

Nevertheless, participants are likely to be advised to be proactive in keeping infections at bay, and so a vaccine testing concern is that not enough trial subjects will get infected, said Dr Paul Offit, director, Vaccine Education Center, Children’s Hospital of Philadelphia, Pennsylvania. Benkeser added if there is low virus transmission, the trial would have to run for longer, or more people would need to be recruited to reach enough infection events.

Another enrolment consideration is trial participant profiles, Benkeser said. On the one hand, older adults should be included, as they are at a high risk of severe manifestations of the disease. On the other hand, recruiting frontline workers, considering their increased exposure, would mean trial results would be collected quicker, he explained. Moderna’s Phase II will enrol 300 participants ages 18–55 years and 300 who are 55 years and older.

Still, if the Phase III is not powered enough to provide insight into efficacy, perhaps a clear safety profile would be sufficient for use in the general public during these unprecedented times, said Offit. In Ebola, vaccines with clean safety profiles are used, and only down the line are they submitted for licensing when there is enough efficacy data, he explained. But Gilbert noted guidance from regulatory authorities with regards to Covid-19 vaccine development has been fairly traditional, in that vaccine approval will hinge on both efficacy and safety.

Covid-19 vaccine approval: Success bar low but several complicating factors

The aforementioned 50% success bar would be enough for Covid-19 vaccine approval, experts agreed. This would be in line with expectations for influenza vaccines, added Offit. In fact, in malaria, even 20–30% protection is acceptable, as it covers a significant chunk of the population, noted Betbeder.

While the lower benchmark is acceptable, the higher bar would boost the vaccine’s likelihood at inducing herd immunity, noted Van der Zeijst. At 50%, a vaccine could be enough to ease both border restrictions and pressure on healthcare facilities, said Edwards.

During the Moderna call, Zaks noted that any registrational trial for a Covid-19 vaccine is likely to use coprimary endpoints that investigate symptom and infection-rate reductions. The infection-driven endpoint may be harder to perform, as subjects would need to come in periodically to be checked for infection, Gilbert said. These tests need to be done frequently—likely more than monthly—considering asymptomatic people can clear the virus quickly, Benkeser added. This underscores the need for better testing facilities, Van der Zeijst noted.

Since there are more asymptomatic than symptomatic cases, perhaps data from the infection-driven coprimary endpoint would be reported first, Van der Zeijst said. Benkeser agreed, explaining that the number of patients required to draw a result on the infection-driven endpoint would be reached before the symptom-driven measure. Asymptomatic infection is estimated at 20–40% of total Covid-19 cases (McMichael TM, et al., N Engl J Med. 2020 Mar 27).

The symptom-driven coprimary endpoint is plucked from experience with influenza vaccine trials, Gilbert explained. From the public’s perspective, this measure may be more valuable as that would mean the vaccine offers protection from developing a moderate-to-severe disease, said Offit. Benkeser concurred but noted the infection-driven endpoint is just as valuable from the perspective of public health outcomes.

Moderna’s Zaks also commented on the importance of a placebo-controlled Phase III, and Gilbert noted subjects could be divided equally between the two arms. The advantage of a 2:1 trial design, though, is there would be more information on surrogate endpoints looking into biomarkers, Gilbert said. These biomarkers could identify which subgroups are most likely to benefit and also would allow a bridging trial in children, doing away with a similarly large Phase III trial, he added.

Moderna’s placebo-controlled Phase II will evaluate safety, reactogenicity and immunogenicity. During Moderna’s call, Zaks said the company is not after a binary event to confirm vaccine efficacy but its vaccine’s risk-benefit evidence would be supplemented by Phase I and II results and potentially surrogate data from animal models.

But Gilbert and Offit noted that Phase III data would be critical for vaccine approval even if Phase II results reveal a spike in antibody titres with the Covid-19 vaccine. This news service’s 16 April article noted that it is still challenging to identify how high a neutralising antibody level is needed for protection, as there can be variation between assays, making it challenging to have a uniform antibody titre target.

Reynald Castaneda is a Senior Reporter 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.