In a world more familiar with the 30% to 70% efficacy rates of seasonal flu vaccines, news of 95% efficacy rates for two of the major late-stage COVID-19 vaccines in development seems thrilling. But do such robust-sounding numbers, the product of relatively early analyses, really merit the enthusiasm they’ve garnered?

Skepticism feels natural in light of the big numbers and their presentation. The claim of 95% efficacy for BNT-162b2, developed by Pfizer Inc. and Biontech SE, for instance, stems from an analysis of just 170 cases of COVID-19 seen among more than 43,000 trial participants. The number of patients on which Moderna Inc.’s 94.5% efficacy claim for was made are even smaller. Furthermore, both announcements were made by press release rather than peer reviewed study, leaving them shielded from close scrutiny.

Nonetheless, the clear consensus of experts consulted by BioWorld this week is that, even with a few caveats for remaining unknowns, the efficacy numbers are credible and even have precedent in the remarkable efficacy of modern measles and tetanus vaccines.

“Spectacular,” is how William Schaffner, professor of infectious disease at Vanderbilt University Medical Center, described the efficacy seen with Moderna and Pfizer’s vaccines so far. Though not 100%, their capacity for protecting the inoculated from severe disease so far looks “superb,” he told BioWorld.

Sarah Hardison, head of product, regulatory and pharmacovigilance at BioWorld's parent Clarivate plc and an immunology expert, concurred. “I’m absolutely floored by the efficacy rates we’ve been seeing,” she said.

Confidence at Pfizer

Still, suspicions around clinical outcomes and their evaluation by regulators, particularly in the U.S., have been a bright thread throughout the pandemic. With science so politicized, the very essence of the scientific method – that some hypotheses turn out to be wrong when they are tested, as happened with hydroxychloroquine and convalescent plasma – has been used to foment distrust. That has clearly touched the vaccine development sphere where, on Nov. 18, Angela Hwang, president of Pfizer Inc.’s biopharmaceuticals group, seemed to anticipate it.

“I think that this efficacy bar of 90%+, 95% is a real one,” she said, during a company conference call held Nov. 19. Furthermore, the high rates are important, “because this is what we need to create the herd immunity around the world so that we can end this pandemic,” she said.

Getting there will require plenty to go right. Fortunately, at least one element, the technology behind the vaccines, messenger RNA (mRNA), is looking strong.

We don’t have any approved vaccines yet that use mRNA technology. “But at a biological level, it could be a really great immunological strategy,” Hardison said. That’s because the method hijacks a recipient’s own cells to generate a substantial amount of Spike protein, the immunogenic component of the virus, right at the localized surface of infected cells. In turn, that draws in macrophages, T cells and other immune cells, which then circulate throughout the body, she said.

Astrazeneca plc and Oxford University’s AZD-1222 vaccine uses a somewhat similar approach to mRNA vaccines but employs a non-replicating adenoviral vector (AAV) to deliver its payload instead of a lipid nanoparticle. Another primary difference is that adenoviral vector delivers a DNA payload. But, while there’s no efficacy data on the Astrazeneca vaccine comparable to the Pfizer or Moderna candidates yet, AZD-1222 could turn out to perform similarly, she said.

A cavalcade of caveats

Efficacy rates alone, however, are just part of a bigger picture. Whether leading COVID-19 vaccines will inhibit or even prevent the transmission of the virus by people who become infected but not ill remains unclear, VUMC’s Schaffner said. So, at least initially, “we don’t think that being vaccinated should make you carefree or careless. We want you to continue to be careful, wear the mask, practice social distancing and avoid large groups,” he said.

Both wide acceptance and wide distribution of approved COVID-19 vaccines will be crucial, too. If those are achieved without sudden adverse events or manufacturing issues cropping up, Thanksgiving 2021 will look near normal, Schaffner said.

Getting to “normal” will also require overcoming skepticism, something that’s “perfectly reasonable,” he said. “These are new vaccines. This is a new virus.”

Furthermore, the lasting imprint of the Tuskegee syphilis study still lives in many minority communities. Many mistrust public health officials’ endeavors to vaccinate them first to address the relatively higher risks minorities have faced in the COVID-19 pandemic, he said, seeing instead an effort to use them as test subject cases ahead of broader vaccine rollouts.

“Even best intentions can be misinterpreted,” he said. “And so we have to be transparent, straightforward, informative, but also reassuring. And we have to enlist the leadership in all the minority communities to not only assist but take the lead.”

The pending return of public health officials as the face of vaccine messaging rather than politicians could help, he said. “That will be going back to a previous norm that has been badly needed throughout COVID,” he said.

Apples and oranges

What of the fashionably maligned flu vaccine? Simply put, the comparison to the apparently-robust COVID-19 vaccines in waiting is probably unfair and certainly without scientific merit. The influenza virus is constantly changing, year to year, flu season to flu season and even during the flu season, Gregg Sylvester, chief medical officer of Seqirus Inc. told BioWorld. Seqirus, part of CSL Ltd., is one of the largest flu vaccine providers in the world.

“For context, each year the World Health Organization (WHO) convenes key stakeholders and provides the recommended four virus strains for inclusion in influenza vaccines the Northern Hemisphere,” something that typically happens in February, he said. Manufacturers then begin the development process based on the WHO-selected strains.

“By the time the flu season begins, the circulating viruses may have changed, thus causing a mismatch between the WHO-recommended virus in the vaccine and the circulating strains. This will impact vaccine effectiveness,” he said.

But Sylvester is far from sour about COVID-19 vaccines’ headline success. “The data we’ve seen in the news regarding the results of COVID-19 vaccines are remarkable,” he said. “We are all cheering for each other to find a vaccine for this terrible pandemic.”

In fact, though focused primarily on flu, Seqirus is even pitching in to make COVID-19 vaccines better, contributing its MF59 adjuvant technology to help broaden the immune response to the virus strains included in a vaccine candidate being developed by the University of Queensland.

What remains to be seen

As with most medical interventions, the passage of time is likely to reveal a more detailed and nuanced picture of COVID-19 vaccine efficacy. “Potentially, the longer we allow the trials to run and the more people who are exposed to COVID-19 and get sick, those efficacy numbers might actually come down a little bit,” Hardison said. With that, we could see COVID-19 vaccines efficacy ultimately fall between that of childhood vaccines, where efficacy rates are over 90%, and annual flu vaccines.

Already, hints of that outcome have been suggested by viral mutations in mink populations. Bidirectional transmission between mink and humans has caused concern that strains could emerge against which the current vaccines offer weaker protection. Still, even weak protection would be a vast improvement from a public health perspective. A vaccine that is good at preventing severe disease would be a game-changer even if it were not as effective at preventing mild or moderate disease.

Further questions remain on matters of transmissibility of SARS-CoV-2 by vaccinated individuals, the impact of comorbidities on efficacy and how various demographics fare with the vaccines ultimately approved. “All of these factors will need to be taken into account to find a truly great vaccine,” Hardison said.

But that will all come later. Today, she said, “we have enough efficacy data. We have enough investigation to have confidence that we can start vaccinating people and end this pandemic.”

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