Johnson & Johnson’s Phase III double-dose Covid-19 vaccine prompted a range of expert analyses as to how the prime-boost regimen would be rolled out considering the single-dose approach is already available in the US. If the company files for an FDA Emergency Use Authorisation (EUA) for the two-dose JNJ-78436735 schedule, experts agreed authorisation is likely but not everyone vouched for broad usage recommendations.

For unvaccinated people, one expert said the two-dose schedule should be recommended for use in everyone given the likeliness it will supersede the single-dose’s efficacy. However, another expert noted single-dose JNJ-78436735 is efficacious enough to alleviate hospitalisation rates, the most relevant metric for policymakers. Two other experts said that the two-dose approach may be reserved for specific subgroups, such as people with comorbidities or high risk of exposure.

For those already vaccinated with single-dose JNJ-78436735 by the time the two-dose regimen is authorised, a fifth expert said that they should not be followed up with for the second jab, as they should be counted as having completed their vaccination schedule. Recommendations from the other four experts fell along the same lines as their comments for those not yet vaccinated, with the first expert adding the second dose could be administered in specific subgroups as much as 120 days later.

In the event of a revaccination campaign owing to waning efficacy, the same expert arguments were pertinent with regards to which of the two vaccine schedules would be deployed. Decisions on which schedule to use, when, and in whom should be based on data and not supply issues, experts cautioned. In fact, they also noted the possibilities that Johnson & Johnson (J&J) does not file an EUA for the two-dose regimen or, if authorised, that the CDC does not promote it at all.

The 30,000-participant Phase III ENSEMBLE 2 trial of the two-dose approach is still recruiting, as per ENSEMBLE 2 is likely to deliver superior efficacy to the single-dose version, experts noted. J&J did not respond to a comment request.

Myriad of scenarios at play with double-dose authorisation

Whether J&J’s two-dose approach should win broad CDC recommendation for use triggered a spectrum of expert analyses. On the one hand, Dr Ali Khan, dean, College of Public Health, University of Nebraska Medical Centre, Omaha, noted there is no reason why a two-dose regimen would not be endorsed for all if it delivers superior benefits compared to the single-dose vaccine.

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If two-dose JNJ-78436735 provides better protection from milder Covid-19 symptoms, against variants of concern and/or longer durability, then it would be tough for regulatory bodies to recommend against the two-dose approach for everyone, said Khan, former director, Officer of Public Health Preparedness and Response at the CDC. Governments value vaccine efficacy against milder forms of disease, as demonstrated by South Africa favouring single-dose JNJ-78436735 versus double-dose AZD1222, which showed suboptimal efficacy against milder Covid-19 symptoms, he noted.

However, Dr Amesh Adalja, assistant professor, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, differed. Given that single-dose JNJ-78436735 offers robust protection against hospitalisation, a second dose may not be needed at all for everyone, he explained. Reducing moderate-to-severe cases is the priority in escaping the acute stages of the pandemic, he added. Phase III ENSEMBLE topline data, announced 29 January, demonstrated that the single dose was 66% efficacious in preventing moderate-to-severe Covid-19. The priority is to get as many people as possible vaccinated, and a single-dose approach is the best way to do so, Adalja noted.

Another two experts were slotted between these extremes. ENSEMBLE 2 reaching at least 90% in its primary endpoint of protection against moderate-to-severe Covid-19 would significantly increase the argument for use of the two-dose approach in all people, said Dr Georges Benjamin, executive director, American Public Health Association, Washington, DC. Still, the value of a single-dose approach would be pertinent for pandemic control, added Benjamin, a former health secretary of Maryland.

Once the two-dose approach is authorised, Dr Mark McClellan, founding director, Duke-Margolis Centre for Health Policy, Duke University, Durham, North Carolina, said it is possible that some people who have already received the first dose should receive the second dose. People with comorbidities and those vulnerable to exposure to variants of concern may benefit from the second dose, he added.

However, Angela Shen, visiting research scientist, Vaccine Education Centre, Children’s Hospital of Philadelphia, Pennsylvania, disagreed, noting people who have already received the single dose should be counted as fully vaccinated. “They are one and done,” added Shen, a retired Captain in the US Public Health Service.

The second dose could be administered later than what ENSEMBLE 2 is investigating, Khan said, allowing the possibility of providing the second dose to those vaccinated with the single dose when it was the only regimen authorised. ENSEMBLE 2 is testing the prime-boost approach with a 57-day gap (8 weeks). The duration between doses could be increased to 60–120 days (8.5–17 weeks), Khan added. In the UK, AZD1222—also an adenovirus-vectored vaccine like JNJ-78436735—is authorised with a possible 12-week gap between doses, while the registrational program included 4–12 weeks between doses.

In the long run, considering a revaccination campaign is possible due to variants of concern or waning vaccine efficacy, experts were also mixed as to which of the two schedules should be deployed. Khan said the prime-boost approach should be used owing to likely superior efficacy benefits. But Benjamin noted perhaps a single-dose approach may be enough to control local outbreaks, particularly in nonvaccinated people. More data is needed, such as the immunogenicity level at certain timepoints after completing a single- or double-dose schedule, McClellan added.

The threshold for redeploying Covid-19 vaccines to address variants of concern is if hospitalisation increases are due to the concerning variants, Adalja noted. Though, this news service reported 12 February, adenovirus-vectored Covid-19 vaccines will have a disadvantage, as antivector responses may stifle efficacy.

Supply-based decisions could undercut credibility to public

Decisions on which subpopulations can receive the two-dose JNJ-78436735 regimen should be based on data and not supply, as the latter would undermine credibility of policy decisions, Benjamin added. ENSEMBLE 2 includes volunteers with comorbidities that are or might be linked with an increased severe Covid-19 risk.

Public pushback is also a potential issue with segmenting the population into those who get the second dose or not, Benjamin noted. People may feel they are not getting the same protection level as those receiving the two-dose schedule, he explained. But there will also be people who would prefer a single dose, like those averse to needles or with side-effect concerns, added Gillian Woollett, senior vice president, Avalere Health, Washington, DC.

J&J’s single-dose approach would remain authorised even if the two-dose approach is authorised, Benjamin noted. Having a single dose is valuable in the face of potential supply limitations, he added. Single-dose JNJ-78436735 has logistical advantages on top of the vaccine not requiring ultralow refrigeration, which makes it easier to deploy in rural parts of the US, Shen said. Single-dose JNJ-78436735 garnered its EUA on 26 February. J&J has a $432bn market cap.

In fact, however, it is not a forgone conclusion J&J will submit an EUA for the double-dose schedule, Shen said. If an EUA application is filed and approved, there is the possible scenario that a double-dose approach may not be rolled out at all. Decisions if a vaccine is rolled out and to which people hinge on advice by the independent Advisory Committee on Immunisation Practices (ACIP) to the CDC.

And even if the CDC establishes guidelines for use, how strictly states adhere to CDC guidance can be variable, Benjamin added. States not wanting to create demand if there is no supply can influence their decisions, he noted.

If the double-dose schedule is not rolled out, ENSEMBLE 2 data would still be helpful in garnering full approval, said Loren Becker, associate principal, vaccine policy and market access, Avalere Health, Washington, DC. ENSEMBLE 2 was officially announced 15 November, while on 9 November Pfizer/BioNTech reported its double-dose Comirnaty vaccine had 90% interim efficacy.

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.