How To Decipher The New Pfizer Study On Vaccines And Variants

(Posted on Friday, January 8, 2021)

One of the biggest and most pressing questions to arise about new SARS-CoV-2 variants like B.1.1.7, the so-called UK variant with 17 distinct mutations, and the so-called South African variant 501.V2 is whether they’ll impact the efficacy of Covid-19 vaccines.

In an attempt to offer some reassurance and possibly some answers, Pfizer has released a new study suggesting that people who have been immunized with their vaccine have antibodies that remain potent against at least one of the more prominent mutations, N501Y. This mutation is one of many that alters the virus’s spike protein and increases its ability to bind to and infect our cells. But there is so much more to the story than just N501Y.

The results of the Pfizer study, published yesterday and still undergoing peer review, are based on blood samples from 20 of the individuals who have already received the Pfizer vaccine. While it’s encouraging to know the Pfizer vaccine seems to be impervious to the effects of at least one significant variant, many more remain in the mix that we’re still unsure about. One such example is E484K, a mutation critical to the South African 501.V2 variant also located in the spike’s receptor-binding domain.

Leaving out these key pieces of the puzzle risks oversimplifying what is actually an incredibly complex issue. Ever since NERVTAG, the British advisory committee tasked with surveilling emerging viral threats, established that the B.1.1.7 variant was up to 70 percent more transmissible than the previously dominant strain, experts have debated whether new variants will present challenges for containing the pandemic beyond increased contagiousness alone. Perhaps the most worrying possibility is that the B.1.1.7 variant, 501.V2 variant, and others like them have evolved to evade the full force of our natural immune responses—diminishing the ability of our antibodies to neutralize and clear out the virus.

Were this true, the extent of the damage wouldn’t end with vaccines and their capacity to fully immunize and protect us. Two of the experimental treatments currently used on critically ill Covid-19 patients, convalescent plasma and monoclonal antibody drugs, rely heavily on preparations of neutralization antibodies to work. Looking at the existing literature on how key SARS-CoV-2 mutations interact with these treatments, both designed to bolster the immunity of their recipients, can give us clues—if not concrete answers—as to how they might impact vaccine-mediated immunity.

Another recently published research paper—also awaiting peer review—mapped how antibodies in several infusions of convalescent plasma were impacted by spike mutations. The spike, we must remember, is not just vital for SARS-CoV-2 and its goal to hijack our cells, but the primary target for both drug and vaccine development. While the main effect of mutation N501Y, an increased affinity for the virus’s favorite cellular receptor ACE-2, didn’t interfere with antibody binding, researchers found that mutations associated with E484, one of the sites left out of the Pfizer study, had the biggest impact on antibody neutralization. In some cases, E484-related mutations reduced the potency of convalescent plasma more than tenfold.

One potential case of immune evasion is documented in more detail in a third preprint study of a man hospitalized with Covid-19 in May 2020 and administered not one, not two, but three rounds of convalescent plasma, among other drugs, over the course of 101 days. During his first hospital stay he appeared to recover, only to be readmitted about a month later due to breathing difficulties and a bad cough. Prior to contracting the virus, the man had already been diagnosed with lymphoma and treated with rituximab, an immunosuppressive therapy. It is possible that with each fresh infusion of antibodies, the virus—given next-to-free reign by a compromised immune system—was able to mutate, grow, and otherwise adapt more effectively than in other hosts.

In other words, what SARS-CoV-2 is currently doing at the population level—navigating a checkerboard of partially immune and immunocompromised human hosts—it was doing in the body of an individual patient. In the time the patient described in the study spent at the hospital, researchers extracted and analyzed more than 20 different viral samples. They observed mutations like the H69-V70 deletion, found in the N-terminal of the spike, that have also been detected in several new European strains. This mutation—like E484K, not included in the strain of virus Pfizer used to study antibodies in vaccinated patients—has also been associated with increased infectivity in the laboratory. The man eventually succumbed to the disease, leading to the likely conclusion that the virus evolved to escape the antibodies present in the convalescent plasma from three different patients.

The new Pfizer study examines several variants that existed before B.1.1.7 and 501.V2 were discovered, with a promise of further research to come. But a much more thorough investigation into not just the E484K mutation and H69-V70 deletion but others, like those in the furin cleavage and others in the N-terminal sites, must be undertaken before we can rest assured that our vaccines, and our immune responses at large, guard us against emergent mutations and resultant strains. Until then, continued vigilance and adherence to public health measures remains of the utmost importance. Better safe, after all, than sorry.

Read full article on Forbes

Originally published on Forbes (January 8, 2021)