Adenovirus-vectored vaccines for Covid-19 are at a disadvantage if vaccination campaigns become periodic to combat new SARS-CoV-2 variants or in the event of low durability, experts said. Antivector immune response is anticipated following the first round of vaccinations and may impact the vaccine’s efficacy if the same vector is used again for revaccinations, they explained.

This news service reported earlier today (11 February) that long-term durability has somewhat taken a backseat in Covid-19 vaccine development owing to new variants of concern arguing the case for repeat vaccinations. Experts flagged that adenovirus-vectored vaccines, on top of having to adjust their antigen to address the new variants, would also have to monitor antivector responses.

Of the adenovirus-vectored vaccine frontrunners, the University of Oxford and AstraZeneca’s AZD1222 may have an advantage in the first round of vaccinations compared to Johnson & Johnson’s JNJ-78436735, CanSino Biologics’ Convidicea (AD5-nCoV) and Russia’s Sputnik V, as AZD1222 is the only vaccine that uses a nonhuman vector. Nonetheless, all these vaccines are still likely to trigger antivector responses, which is likely to dilute their efficacy during revaccinations, experts noted.

While antivector response is a concern, it is hard to pinpoint if this issue needs to be addressed imminently, experts said. Concerns stem from the experience with adenovirus infections, which lead to protection from further infections, they said. This news service reported 18 June that one can get a maximum of two doses of such vectored vaccines over a lifetime; any more and the immune system could generate neutralising antibodies against the vector. However, not all experts agreed that experience from infections can be extrapolated to adenoviruses used as a vaccine vector.

There are ways to curb antivector responses, such as manipulating the vector itself for the second round of vaccinations or in the initial vaccination stage, combining an adenovirus-vectored vaccine with a different technology in the prime-boost approach or manipulating doses, experts said. However, due to limited data, it may be judicious for vaccine receivers to switch vaccine technologies in the next round of vaccinations, they added.

The aforementioned companies and institutions did not respond to a comment request.

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AZD1222 has some benefit on pre-existing immunity to first round of vaccinations

Human and chimpanzee adenovirus vectors do not naturally lend themselves to repeat dosing compared with other vaccine technologies, as adenoviruses are also pathogens themselves, said Alan Parker, PhD, reader in virology, School of Medicine, Cardiff University. When adenoviruses are used as a delivery agent, there is likely to be an antivector immune system response, added Eric Kremer, PhD, adenovirus virologist, Institut de Génétique Moléculaire de Montpellier, France. Hence, there is potential for the immune system to build immunity against the vector with repeat dosing, which could then decrease vaccine efficacy, noted Parker.

AZD1222 has an advantage, since it features chimpanzee adenovirus vectors and people do not typically have pre-existing immunological memory against this vector, Parker and Kremer said. Ad5, however—the vector in CanSino’s Convidicea—is prominent in sub-Saharan Africa; about 90% of people have pre-existing antibodies against this serotype, and so such a vaccine would not be ideal in this region, Parker noted.

In contrast, Ad5 seroprevalence may only be around 30% in western countries, he added. Convidicea has emergency authorisation in China and is in three ex-China trials that together are recruiting in Canada, Latin America, Pakistan and Russia. CanSino’s China-based trials divided patients according to their pre-existing Ad5 antibodies, said Richard Webby, PhD, director, WHO Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds, Memphis, Tennessee. Yet, establishing such a screening system in practice adds a logistical issue, particularly at the large scale needed, he added.

An additional concern with Ad5, based on experience in HIV, is that vaccinated men experienced increased susceptibility to an HIV infection, said Dr Susan Buchbinder, director, Bridge HIV, San Francisco Department of Public Health. Among the theories behind this observation is that the vector may activate immune system cells that bolstered the chance of an HIV infection, though it is unclear if this would apply to SARS-CoV-2, she added.

Ad26, J&J’s vector, is rare in North America and Europe, but there is high seroprevalence in Africa and Asia, Kremer noted. In fact, the reason JNJ-78436735’s South Africa data shows lower efficacy may be not only because of the B.1.351 variant, first identified in that country and found to be more transmissible, but also potentially due to Ad26 being prominent in the region, said Dr Hildegund Ertl, professor, Vaccine and Immunotherapy Centre, The Wistar Institute, Philadelphia, Pennsylvania. On 29 January, J&J reported that the Phase III ENSEMBLE trial investigating a single dose showed that in South Africa, the level of protection against moderate-to-severe Covid-19 was 57%, whereas this was 72% in the US and 66% in Latin America.

Antivector response is likely to be further cemented in the first round of vaccinations if the same vector is used in the prime-boost approach, Kremer added. AZD1222 and JNJ-78436735 were initially envisioned as single-dose vaccines, but a booster was added. While J&J continued development of the single-shot regimen, AZ has focused on the two-dose vaccine. CanSino’s vaccine is authorised as a single dose but is under investigation as single and double dose.

A long gap between injections may mean antivector immunity caused by the primer could wane by the time the booster is administered, said Dr David Curiel, director, Biologics Therapeutic Centre, Washington University School of Medicine, St Louis, Missouri. But, delaying the booster of the same adenovirus vector may not assist in easing antivector concerns for revaccinations, Kremer added.

Timelines as to when vectors expire unclear

Despite concerns regarding antivector response, experts were divided as to how immediately this should be addressed. Parker and Kremer, who have used adenovirus vectors in the context of gene therapy, agree that pre-existing antibodies may be a forthcoming issue in the second round of Covid-19 vaccinations. With these vaccines, there is not only the need to monitor immunological data against the SARS-CoV-2 antigen but also against the vector, added Ertl.

Yet Ertl noted that modifications may not be an immediate need, even for the second round of vaccinations. Even if there is antivector immunity from the first round of vaccinations, there would still be efficacy in the second round and so it may not be a reason to change, Curiel agreed.

Specific timelines to decipher when the vector is unusable are hard to pinpoint, Parker said. There is limited data to understand adenoviruses’ lifecycle in humans, Kremer agreed. But, based on animal studies, an adenovirus infection develops the same way as other viral infections, which could mean reduced efficacy in round two of vaccinations, he added. But, Parker said, using adenovirus infections as a predictor for how quickly a vector may be ineffective could be flawed. The immunological response against the vector may be different compared to a natural pathogenic infection, he explained.

William Wold, PhD, chairman, Molecular Microbiology and Immunology, St Louis University, Missouri, though, explained that while an adenovirus infection leads to tens of thousands of viral progeny to spark a robust immune system response, vaccines may have doses high enough to trigger comparable immune system response.

Vector, strategy modifications likely needed

Due to uncertainty if the adenovirus vector would still be appropriate for revaccinations, the vectors—including chimpanzee adenovirus vectors—may need to be subtly modified if a second round of vaccinations is needed, Parker said. It is not challenging to manipulate the outside of the adenovirus vector, Curiel said. In fact, a chimera of Ad3 and Ad5 could be made to traverse Ad5 antivector immunity, he added.

But every time there is a modification to the vaccine, additional studies would need to be done, Kremer said. The new version may only need to demonstrate noninferior immunogenicity versus the prior version to maintain authorisation, said Curiel. Yet, there is no correlative data between Covid-19 immunogenicity and protection. Adenovirus-vectored vaccines’ safety profile is encouraging so far, with long-term concerns assuaged given that the doses are low enough to not raise flags, Parker added.

To delay antivector responses from reducing vaccine efficacy, perhaps using two different vectors for the prime-boost approach would be worthy, Kremer and Curiel said. Sputnik V uses Ad5 and Ad26 vectors in its two-dose regimen. On 11 December, Russian Direct Investment Fund and Gamaleya Research Institute of Epidemiology and Microbiology announced AstraZeneca accepted their proposal to use Sputnik V’s Ad26 component in combination with AZD1222.

Another approach to curb antivector responses is demonstrated by some data from pooled analysis of late-phase AZD1222 trials in the UK and Brazil, Webby said. In participants who received two standard doses, vaccine efficacy was 62.1%. But in volunteers who received half dose of the primer, efficacy was 27.9 points higher (p=0.010). One possible reason for this discrepancy is lower antivector immunity from the first dose, the paper states (Voysey, M, et al., Lancet. 2021 Jan 9;397(10269):99-111).

With such adenovirus vector-related blind spots, it would be ideal if vaccine receivers switch to a different vaccine technology altogether in the event a second round of vaccinations is needed, Wold and Kremer said. On 4 February, the UK’s National Institute of Health Research initiated a study investigating combinations of different vaccine technologies, with AZD1222 plus Pfizer (NYSE:PFE)/BioNTech’s (NASDAQ:BNTX) mRNA vaccine, Comirnaty (BNT162b2), being the first combination to be evaluated. The other authorised mRNA vaccine is Moderna’s (NASDAQ:MRNA) mRNA-1273.

A person can also switch to a different adenovirus-vectored vaccine, Parker added. Looking further ahead, there are at least 100 rare human adenovirus serotypes available that could potentially be developed as a new vaccine, Parker added. There are also other chimpanzee adenovirus subtypes available, Kremer noted.

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.