Non-human primate data shed light on correlates of protection and duration of immunity to COVID-19 vaccines

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Two more COVID vaccine developers have published non-human primate data suggesting efficacy, bringing the total to five. One of the new papers builds on the case for neutralizing antibodies as key correlates of protection; the other suggests immunity can last at least three months.

On Thursday, a Nature article describing Ad26.COV2.S from Johnson & Johnson (NYSE:JNJ) linked higher titers of neutralizing antibodies against SARS-CoV-2 to lower levels of the virus in the lungs of rhesus macaques, without a requirement for strong T cell responses.

The paper aligns with findings from Moderna Inc. (NASDAQ:MRNA) and NIH published Tuesday that showed mRNA-1273 also controlled viral replication without inducing a strong CD8+ T cell response. Together, the findings argue neutralizing antibodies may be sufficient to confer protection, a major outstanding question in the field (see “Moderna’s COVID-19 Vaccine Protects Monkeys”).

The Moderna and Johnson & Johnson papers also reveal the companies’ vaccines both deliver the full-length spike protein engineered with same two mutations. The high degree of similarity between the antigens will put the vaccines’ modalities on display, as one uses lipid nanoparticle RNA delivery and the other uses viral vector gene delivery.

The second paper published Thursday in bioRxiv demonstrated that INO-4800 from Inovio Pharmaceuticals Inc. (NASDAQ:INO) induced immunity that persisted for at least three months after vaccination, the farthest out any group has reported to date.

Ad26.COV2.S is in Phase I/II testing, and J&J expects to start a Phase III trial in September. Inovio plans to advance INO-4800 from Phase I to a Phase II/III study this summer. The pair is not far behind mRNA-1273 or BNT162b2 from partners Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX), both of which entered pivotal trials this month (see “Two Lead mRNA Vaccines Enter Pivotal Testing for COVID-19”).

J&J vaccine efficacy

A team led by Harvard’s Beth Israel Deaconess Medical Center researchers, and included Janssen scientists, demonstrated Ad26.COV2.S was effective after a single immunization in rhesus macaques.

J&J is testing single and prime-boost administrations of Ad26.COV2.S in its clinical trials.

So far, all the vaccines that have reported human data appear to require two doses for efficacy. If J&J can use a single dose, it would decrease the burden on manufacturing scale-up (see “Comparing Clinical Data from COVID-19 Vaccines”).

The researchers evaluated six other variants of the adenovirus vaccine encoding different versions of the full-length SARS-CoV-2 spike and found Ad26.COV2.S induced the highest neutralizing antibody titers and was the most protective against viral replication.

None of the six vaccinated animals challenged with SARS-CoV-2 had detectable viral RNA in lung fluid at any time point; and only one had detectable viral RNA in the nose, which was gone by day four. All 20 control animals had detectable viral RNA in lung and nasal samples.

Across all the seven vaccine groups, higher neutralization titers correlated with lower peak virus levels in the lungs and nose.

Among the vaccine variants, Ad26.COV2.S -- the construct most like Moderna’s mRNA-1273 -- led to the lowest CD4+ and CD8 T+ cell responses against SARS-CoV-2.

The lack of correlation between protection and T cell responses in the Ad26.COV2.S study strengthens the case made in Moderna the paper that neutralizing antibody responses may be the major correlate of protection.

At least three other COVID-19 vaccines have been shown to induce T cell responses: AZD1222 from AstraZeneca plc (LSE:AZN; NYSE:AZN) and Oxford University; BNT162b1, another candidate in Pfizer’s and BioNTech’s COVID-19 vaccine program; and Ad5-nCoV from CanSino Biologics Inc. (HKEX:6185).

The Moderna and J&J findings do not rule out the possibility that T cells play important roles in the mechanisms of those programs (see “Readouts Raise Expectations”).

Inovio vaccine durability

The data from Inovio’s INO-4800 appear weaker than from mRNA-1273 and Ad26.COV2.S, but the timing of the challenge suggests immunity against SARS-CoV-2 can last at least three months.

The natural history of COVID-19 is still largely unknown and several groups have reported reduced levels of antibodies against SARS-CoV-2 within a few months of recovery.

Inovio immunized rhesus macaques twice with INO-4800 and challenged the monkeys 13 weeks later. Other developers have challenged non-human primates 4-6 weeks after the last vaccination.

Neutralizing antibody titers and reactive T cell numbers peaked two weeks after boost -- 11 weeks before challenge -- but the challenge induced spike-specific neutralizing titers and T cell numbers above the vaccine-induced levels, suggesting immune memory had developed.

Three of the five monkeys had detectable viral RNA in the lungs, which peaked at day two or three after infection; one still had detectable virus seven days after infection. By contrast, all unvaccinated animals had detectable viral RNA in the lungs four a minimum of four days after challenge.

All five immunized macaques had detectable virus in the nose, and similar peak nasal loads as the control animals.

A little more AZ data

Also on Thursday, Nature published a peer-reviewed version of a study of AZD1222 from AstraZeneca plc (LSE:AZN; NYSE:AZN) and Oxford University that had originally been reported as a preprint in bioRxiv (see “Preclinical Data for Oxford Vaccine”).

The peer-reviewed article adds data from macaques immunized in a prime-boost regimen. The second vaccination boosted neutralizing titers from 5-40 to 10-160.

Five out of six animals vaccinated twice had undetectable levels of virus three days after challenge. Like Inovio’s vaccine, all six had nasal virus levels similar to control animals.

AZD1222, mRNA-1273, BNT162b2 and Ad26.COV2.S, but not INO-4800, have support from the U.S.’s Operation Warp Speed (see “How Warp Speed’s Deals Stack Up”).

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