On Sept. 17, the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) rejected (16–2) Pfizer’s supplemental biological license application (BLA) for a third COVID-19 dose for all Americans age 16 and older six months after completion of the primary series of shots. VRBPAC then voted unanimously (18–0) to expand the emergency use authorization (EUA) to include a third dose for individuals 65 years of age and older and for individuals at high risk of severe COVID-19.

On Sept. 22, FDA amended the emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine to allow for “use of a single booster dose, to be administered at least six months after completion of the primary series in individuals 65 years of age and older; individuals 18 through 64 years of age at high risk of severe COVID-19; and individuals 18 through 64 years of age whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19 including severe COVID-19.”

On Sept. 23, the Advisory Committee on Immunization Practices (ACIP), part of the Centers for Disease Control and Prevention (CDC), issued formal recommendations for a third dose of the Pfizer product in people who have already received two Pfizer doses who are 65 or older, or who live in long-term care facilities, as well as people ages 18 and up who have underlying medical conditions that make severe disease more likely for them.

ACIP chose not to recommend a third dose for people who do not have underlying medical conditions themselves, but face greater potential exposure to viruses through their work. Late that night, CDC Director Rochelle Walensky overruled ACIP and issued a recommendation for the high-exposure, healthy group as well.

Paucity of data

Both meetings (VBRPAC and ACIP) were fraught with frustration as committee members grappled with poor or missing data about vaccine efficacy against variants, antibody levels in double-dosed and triple-dosed individuals, and immunological factors correlated with protection against disease.

VRBPAC members struggled to reconcile data presented by Dr. Sharon Alroy Preis and Dr. Ron Milo from Israel – which appeared to show that individuals who have had two Pfizer shots are at nearly the same risk of hospitalization as unvaccinated individuals – and CDC data that seem to show Americans with two Pfizer shots have a greatly reduced risk of hospitalization compared with their unvaccinated counterparts.

Data from Israel suggest that people who have had two Pfizer shots may be as likely to contract the novel coronavirus, and nearly as likely to be hospitalized, as unvaccinated people. Roughly 80 percent of Israelis have received two shots, mostly of the Pfizer product; 60 percent of hospitalized coronavirus patients in Israel have received two shots. Recent death data from Public Health England paint a similar picture, as shown in the accompanying chart.

However, the CDC has consistently reported significantly lower odds of hospitalization among Americans who have received two shots of the Pfizer product, a data point highlighted in an editorial published Sept. 14 in The Lancet, co-authored by two high-ranking FDA staff who quit the agency – according to insiders – over what they viewed as an overly politicized vaccine approval process. “[V]accination appears to be substantially protective against severe disease from all the main viral variants,” Marion Gruber and her colleagues assert (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02046-8/fulltext).

Reports on breakthrough infections of fully vaccinated Americans from the federal Centers for Disease Control and Prevention (CDC) use data from a pastiche of states and counties. Hospital staff in Pennsylvania have found that COVID-19 shot information is often unavailable or incorrect in the databases they consult, as reported in the Philadelphia Inquirer Sept. 12. Israel and England, on the other hand, have fully-fledged national vaccination registries.

Three factors may be at play in the appearance of breakthrough infections-waning immunity, viral variants, and antibody-dependent enhancement-and VRBPAC members felt uncomfortable placing a large bet on waning immunity, at least at present.

Waning immunity

As discussed in our previous coverage of COVID-19 shots and antibodies (https://www.lvpnews.com/20210518/did-your-coronavirus-shot-work/), virus-specific, circulating antibodies decrease over time. The duration of high antibody levels for the three COVID-19 vaccines distributed in the U.S. is not known.

Two vocal believers in the theory that waning immunity is driving coronavirus hospitalizations in vaccinated people are Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), and current Israeli “coronavirus czar” Professor Salman Zarka. As reported Sept. 3 in the Jerusalem Post, Israel changed the definition of a “fully vaccinated” person from someone who has received two doses of the Pfizer mRNA product, to someone whose two Pfizer doses were within the past six months, or a person who has received a third mRNA shot more recently.

Israel also considers people who have recovered from COVID-19 in the past six months, or who recovered more than six months ago but received a single mRNA shot after recovery, to be “fully vaccinated.” Zarka has even hinted that a fourth shot may be coming for Israelis in the near future.

‘Escape variants’

Coronaviruses like SARS-CoV-2, the virus that causes COVID-19, have four different proteins as part of their structure. The current vaccines cause the body to produce antibodies against the spike protein, often called “S.” An antigen is a molecule or molecular structure that can be bound by an antigen-specific antibody or an antigen receptor. There are multiple antigens on the S protein. These antigens can change shape (mutate), which means that the spike protein does not, on a molecular level, look the same in viral samples collected many months apart.

In other words, it is an oversimplification to say that a person has produced “antibodies to the S protein.” In reality, the person has produced antibodies that bind to some of the many antigens on the two subunits of the S protein.

“Antigenic drift” is the term virologists use to describe the process by which viral proteins gradually change their shape. “Antigenic shift” involves gene reassortment between variants within a host co-infected with more than one variant, resulting in more significant changes. Both types of changes may be occurring in SARS-CoV-2.

One of the most vocal critics of the COVID-19 mass vaccination campaigns has been Dr. Geert Vanden Bossche. He has a degree in veterinary medicine from the University of Ghent and a PhD in virology from the University of Hohenheim, and has worked for several vaccine manufacturers, including Novartis, as well as the Global Alliance for Vaccines and Immunization (GAVI).

Beginning in February 2021, Vanden Bossche began publishing arguments against the mass use of COVID-19 shots in the middle of the current pandemic. Acknowledging that these shots induce the recipients to generate antibodies against antigens present in the original Wuhan strain of the novel coronavirus, Vanden Bossche asserted that inducing this very limited kind of immune response in wide swaths of the population will create “immune pressure” on the virus, helping it to mutate in ways that evade these antibodies, increasing the risk of infection with future variants among both vaccinated people and people who have recovered from COVID-19.

When a high percentage of the population has an immature immune response, Vanden Bossche argues, antigenic drift preferentially favors variants that are successful in breaking through the immature and highly specific (to the antigens of an old variant) immune response in vaccinated people. The result is a reduction in the number of circulating variants, with the persistent variants being the ones that the population’s antibodies do not neutralize.

During the Sept. 18 meeting, VRBPAC members asked why Pfizer has not offered a variant-specific dose in addition to, or instead of, a third dose of the original product. Dr. Cody Meissner of Boston Children’s Hospital inquired, “For a booster vaccine, shouldn’t we try to match the predominant strain as closely as we can, which is right now, the Delta strain? So why did Pfizer decide on BNT162b2? Because if a new variant emerges, don’t we want to match the new strains that are most likely to circulate, as closely as possible?”

No one from Pfizer offered a response at the VRBPAC meeting; it is not clear whether the trials Pfizer had planned to initiate in August have even begun.

Antibody-dependent

enhancement

Prior to the EUA of any COVID-19 vaccine, some researchers raised the alarm that previous attempts to create vaccines against coronaviruses had created “antibody-dependent enhancement” (ADE) in recipients. In other words, the vaccine made them sicker than they would have been without it. In March 2020, the Journal of Virology published an article from a team of scientists based in the United States and in China, including two employees of the Wuhan Institute of Virology, noting that ADE was observed during the attempts to create vaccines for Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), two other coronaviruses. The researchers explain that neutralizing antibodies induced by vaccination binds to the surface spike protein of coronaviruses, triggering “a conformational change” of the spike protein, and helping the virus to enter a cell.

In Dec. 2020, researchers Jing Zhao et al sounded a warning about vaccines that use the full S protein: “Due to the taxonomic and structural similarities between SARS-CoV, MERS-CoV, and SARS-COV-2, ADE is an issue that should be considered seriously in designing MERS-CoV and SARS-CoV-2 vaccines, particularly those with a full-length S protein. Neutralizing epitopes could elicit a more robust protective immunity but less or no ADE side-effects.” (The Pfizer and Moderna products instruct the body of the recipient to manufacture the full S protein; the J&J product introduces the S protein into the body via an adenovirus vector.)

Where we are now

VRBPAC member Dr. Hayley Gans, who is a professor of pediatrics at Stanford University, captured the concerns voiced by many advisory committee members with her comments toward the end of the day-long meeting.

“I am struck by FDA asking us to look at the totality of evidence,” Gans said, “when there’s several key points that we’re lacking right now. One of them is the very strong safety data that we could have, actually, with one million third doses that have been given [to immunocompromised Americans under the existing EUA…] That’s a really missed opportunity and something that should be considered when FDA considers that these 300 people [from trial data submitted by Pfizer with its supplemental BLA] is not a large enough study.”

Gans continued, “Along with Dr. [James] Hildreth, [I believe] another missed opportunity that I think FDA could have asked for is looking at both humoral and T-cell immunity. We really could […] have the answers, and to be told that ‘they’re complicated assays’ or ‘it’s up and coming’ is … feels that we’re making decisions when there’s data out there that we’re not [being given].”

From a practical standpoint, doctors continue to contend with the challenge of treating patients hospitalized with COVID-19, regardless of vaccination status. Dr. Hamid Merchant, pharmaceutical scientist and subject leader in pharmacy at the University of Huddersfield in U.K., spoke with the Press about the inadequacy of hospital treatments. "In an analysis of recent vaccine surveillance data from Public Health England, he showed that 97 percent of fully vaccinated individuals who died were aged 50 or older. Prior to the vaccine rollout in the UK, 98 percent of COVID-19-associated deaths were also in individuals aged 50 or above, as Dr. Merchant and colleagues noted in a Feb. 2021 publication (https://doi.org/10.1080/17476348.2021.1890035)."

The published paper only has the 2020 data, not the 2021 data. (The 2021 data is verifiable, though, on the PHE website.)

Merchant tells the Press that the elderly population is still at the most risk of severe coronavirus disease and death despite vaccination, and that this group still needs protection. He recommends that public health authorities look beyond vaccines to protect the most vulnerable in society, citing therapies such as antiviral drugs or monoclonal antibodies (mAbs) to be considered within 24 hours of catching the virus in all high-risk individuals, regardless of vaccination status.

Merchant also suggested that doctors consider giving mAbs to all high-risk populations as a form of passive immunization. On Sept. 16, the U.S. FDA expanded its EUA for a duo of mAbs, bamlanivimab and etesevimab, to include post-exposure prophylaxis in certain high-risk groups.