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Preclinical data suggest Oxford vaccine could reduce COVID-19 symptoms, won’t provide herd immunity

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Preclinical data from a leading COVID-19 vaccine candidate from Oxford University suggest that it may be more like the flu vaccine than the smallpox jab, reducing the severity of symptoms but not preventing infection.

Such a vaccine could help individuals infected with SARS-CoV-2 avoid pneumonia and the downward spiral that all too frequently leads to a ventilator. It would save lives, especially among the most vulnerable, such as the elderly and people with diabetes and other health conditions that put them at high risk of succumbing to COVID-19.

A partially effective vaccine would not, however, break the spread of infection. It wouldn’t provide the herd immunity that politicians and pundits promise when they tell the public that a vaccine will give them their normal lives back.

A vaccine that reduces symptoms takes longer, and many more patients, to test than one that halts the virus entirely, John Mascola, head of the Vaccine Research Center at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), told BioCentury.

Asymptomatic infection is estimated to represent 20% to 40% of COVID-19 cases, according to a May 11 Science paper authored by Mascola; Lawrence Corey, president emeritus at the Fred Hutchinson Research Center; NIAID Director Anthony Fauci; and NIH Director Francis Collins. As a result, assessing reduction of disease severity as a primary endpoint will be complex, with initial efficacy trials requiring large initial enrollment and ongoing monitoring of serological and clinical endpoints.

The Oxford vaccine is one of the most advanced; at least nine other vaccines are in clinical development for COVID-19, according to BioCentury’s COVID-19 Resource Center. Of these, two are slated to have readouts and potentially be available for either large-scale deployment in Phase III trials, or possibly for distribution under FDA Emergency Use Authorizations by year-end.

The two, both mRNA vaccines, are mRNA-1273 from Moderna Inc. (NASDAQ:MRNA) and NIH, and BNT-162 from BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE) (see “End of the Beginning for COVID-19 Vaccines”).

Four of the COVID-19 vaccines in clinical trials are being developed by Chinese companies (see “China emerging as a leader in COVID-19 vaccines”).

Half-full or half-empty?

NIH emphasized the positive in a May 15 press release describing data about the ChAdOx1 nCoV-19 vaccine that is being developed by the Oxford team with Vaccitech Ltd.

“A single dose of ChAdOx1 nCoV-19, an investigational vaccine against SARS-CoV-2, has protected six rhesus macaques from pneumonia caused by the virus,” NIH stated in a press release.

NIH cited a BioRxiv preprint that demonstrates a single dose of ChAdOx1 nCoV-19 “rapidly induced immune responses against SARS-CoV-2 in mice and rhesus macaques.”

ChAdOx1 nCoV-19 did not produce antibody enhancement, alleviating a major safety concern about COVID-19 vaccines.

All six vaccinated monkeys produced virus-neutralizing antibodies, with titers ranging from 5 to 40, while none of the three control monkeys produced neutralizing antibodies.

Three of the vaccinated monkeys developed an elevated respiratory rate, a sign of clinical disease. The control monkeys had worse clinical scores for a longer period of time, suggesting the vaccine had decreased disease severity.

Animals received a single dose of 2.5 x 1010 virus particles, half the dose being administered in clinical trials of the vaccine.

The authors’ conclusion was that the single vaccination was effective in preventing damage to the lungs. They also postulated that the low levels of virus in the bronchoalveolar lavage (BAL) and lung tissue of vaccinated animals compared with controls could indicate the vaccine blocks viral replication in the lower lungs. However, the viral load in nasal secretions was not different from controls, indicating the animals were similarly infected upon challenge.

The results fall short of the hopes, not to mention hype, associated with this vaccine.

William Haseltine, who founded Human Genome Sciences, an early genomics company that was acquired by GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) in 2012, presented a less rosy perspective, writing in Forbes. Haseltine referred to the titers of neutralizing antibodies induced by the vaccine as “extremely low.” He asserted that because the Oxford vaccine did not provide sterilizing immunity against virus challenge, it failed to achieve the “gold standard for any vaccine.”

The Phase I/II trial of ChAdOx1 nCoV-19 is testing both a single dose and a prime boost regimen in healthy human volunteers.

Non-human primate challenge trials with a two-dose “prime boost” regimen of the vaccine are under way, Adrian Hill, director of Oxford’s Jenner Institute, said May 13 on a webinar sponsored by the Duke-Margolis/Alexandria Summit.

Better than nothing

Setting expectations could be as important as creating vaccines and therapies. Vaccines will do no good if they are shunned by a public that is confused about the efficacy or disappointed by anything less than complete protection.

Leaders of the vaccine development initiatives have made it clear that when it comes to fighting COVID-19 they won’t make the perfect the enemy of the good.

“A product that has really good efficacy would be delightful,” Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, said on the Duke-Margolis webinar. “Something that can get to herd immunity would be really nice, but we’ll take what we can get.”

Phase III COVID-19 trial designs haven’t been finalized; however, there is a consensus that they will be powered to detect improvements in symptoms, Mascola told BioCentury. At NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) consortium, the working group’s consensus in designing trials is to “power the study to have an ability to know if [candidates] protect against severe disease.”

“The general idea will be to measure as many things as we can to see if [a vaccine candidate] prevents people from becoming virus positive at all, or if it prevents people from getting severe symptoms,” Mascola said. “That may be enough.”

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