Boosters: Laboratory Evidence Needs to be Balanced with Field-based Data

This article is the third in a three-part series on COVID-19 booster vaccines, which is an evolving discussion as more evidence emerges about the performance of vaccines against variants.

Alongside the heated policy debate over the disproportionate consumption of COVID vaccines in rich countries, a handful of senior scientists are pushing back against the scientific rationale of offering booster vaccines to healthy people who are already fully vaccinated.  

They argue that a key metric touted by booster shot proponents – lab-based antibody counts in the blood – is not a watertight proxy for the real-life performance of vaccines. 

Dr Francis Collins, the Director of the US National Institutes of Health (NIH), has recently argued in his blog that immunity against SARS-CoV-2 and variants like Delta could even last “for years”.

At the heart of this scientific debate is the question of whether the “neutralizing antibody” counts in blood are an accurate proxy of immunity against COVID-19. Like warriors, these antibodies latch onto foreign invaders such as the SARS-COV-2 virus and block their entry into human cells, preventing them from wreaking havoc in the body. But they also are not the only factor in the body’s immune response, experts told Health Policy Watch.

The debate continues to rage even as Pfizer/BioNTech prepare to submit a request to the US Food and Drug Administration for approval of a third booster, based primarily on just that kind of neutralizing antibody data. 

Neutralizing antibodies (green) can latch onto viruses like SARS-CoV-2 and prevent them from entering human cells

Lab antibody responses are not a proxy for immunity

But until more robust evidence emerges, antibody responses from the lab can’t yet be used as a simple benchmark to boil down a complex immune response or to estimate the extent to which a person is protected to SARS-CoV-2, Dr Michael Osterholm, Director of the US Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, told Health Policy Watch in an interview.

“You can do all the lab studies you want, but if you can’t demonstrate in humans that antibody responses are the core of their protection against SARS-CoV-2, then the question is what are you measuring?” said Osterholm. “You can have the most amazing immunological response you want, but if that’s not what’s protecting you, what good is it?”

Surprisingly, early-stage clinical trials for mRNA vaccines have revealed that people are well protected against SARS-CoV-2 within three weeks of their first jab, yet their antibody counts are very low at that point, said Osterholm. This indicates that antibodies on their own can’t fully explain or predict immunity to COVID, at least for now, he added.

“During the early mRNA trials [of Pfizer and Moderna vaccines], the antibody response was not at all correlated with very rapid protection from the vaccines, even at three weeks post first dose, where we already saw a trend towards protection,” explained Osterholm.

“I am not totally convinced that there is perfect parallelism between measures of antibodies and immune response,” added Dr Antoine Flahault, Director of Geneva University’s Institute of Global Health. “There is a lot of evidence in the past history of infectious diseases where such parallelism did not exist.”

It is also a well-known fact among immunologists that antibody counts naturally wane over time following a natural infection or vaccination, but upon re-exposure to a pathogen like SARS-CoV-2, the immune system will mount a quicker and more robust response. This includes massive antibody production that will help neutralize the pathogen, researchers told Health Policy Watch.

Robust immunity may last ‘for years to come’

Last month, NIH director Collins asserted that robust immunity against SARS-CoV-2 could persist “for years”, even against rapidly spreading variants.

Collins was citing an NIH-supported study of 14 fully vaccinated individuals, which revealed that the “germinal centres” in lymph nodes – the training camps where an army of diverse immune cells learns to fight off threats like the SARS-CoV-2 virus – were highly active several months after vaccination, including in people infected with Alpha and Beta (the variants first discovered in the UK and South Africa, respectively). 

“Germinal center reactions that persist for several months or longer usually indicate an extremely vigorous immune response that culminates in the production of large numbers of long-lasting immune cells, called memory B cells,” said Collins.

“Some memory B cells can survive for years or even decades, which gives them the capacity to respond multiple times to the same infectious agent….vaccine protection looks really good right now, including for the delta variant that has all of us concerned.”

Israel set to be world’s guinea pig on booster shots 

Meanwhile in Israel, where cases are rising rapidly even though the country’s vaccination coverage is one of the highest in the world, Dr Eyal Leshem stressed that robust clinical data is still lacking about the real-life benefits of boosters in fully vaccinated people.

“We cannot rely on surrogate markers like seroconversion or neutralizing antibodies to provide a general recommendation for a booster dose,” emphasized Leshem, who is at the helm of the Center for Travel Medicine and Tropical Diseases at the Sheba Medical Center in Israel. “This must be proven clinically, it cannot be based on hunch.”

His comments come as Israel prepares to offer a third booster shot to anyone aged 60 and over this week as a precautionary move in light of a sharp increase from about 200 daily cases in early July to almost 3 000 a day by early August. 

Israel is also concerned about data revealing that the efficacy of two-doses of the Pfizer/BioNTech vaccine has dropped from over 90% to around 40% for the prevention of infection.

That data has sparked concerns that people over the age of 60, who tend to have weaker immune systems and more pre-existing conditions than younger people, need stronger protection, even if 90% of them are already fully vaccinated.

Leshem added that boosters would only be warranted if they were shown to substantially improve primary clinical outcomes like severe disease and hospitalization, rather than secondary outcomes like infection and mild disease – or even results from lab-based studies like antibody counts.

Based on his assessment, the data to support boosters in healthy people appears to be lackluster for now – insofar as two shots of Pfizer confer more than 95% protection against severe COVID-19, even against variants like Alpha, Beta, and most recently Delta.

“The bulk of epidemiologic evidence supports real-life effectiveness of vaccines against severe disease and hospitalization,” emphasized Leshem. “Studies by Public Health England suggest 95% effectiveness against hospitalization against Delta.”

Soon, more large-scale clinical data about the benefits of boosters will become available, as Israel starts administering boosters to people over 60 in the next few months.

While Israeli experts acknowledge that they are taking a gamble with boosters – initial results suggest that they are at least not harmful in people who receive them, based on the lack of adverse effects seen among immuno-compromised people who have already received boosters in France and Israel.

The United Kingdom, which has currently seen some of the highest case counts worldwide even though over half of the population is fully vaccinated, may soon follow with boosters in high-risk groups, as well as Germany, Spain, and Italy.

Meanwhile, in the United States, where regulatory authorities are holding back against a booster for now, there are concerns that people will seek a third shot on their own. This is possible given the fragmented nature of the US health care system, which enables people to receive their third jab at a different clinic or pharmacy than the one that they used for their first two – at least in theory.

Such behavior will be challenging to track in the US, as the country lacks a centralized database of who has been vaccinated, when, and with how many doses – unlike Israel, which has a detailed database that can track the vaccination status of virtually every citizen and resident in the country.

Pfizer pushes US for booster shots in general population 

Pfizer/BioNTech, meanwhile, is already pushing the US drug regulatory agency to consider boosters in the general population and developing an updated booster to target the Delta variant, citing “encouraging” lab-based data to support the move.

“Pfizer and BioNTech have seen encouraging data in the ongoing booster trial of a third dose of the current BNT162b2 vaccine,” said a recent statement by Pfizer/BioNTech. “Initial data from the study demonstrate that a booster dose given 6 months after the second dose has a consistent tolerability profile while eliciting high neutralization titers against the wild type and the Beta variant, which are 5 to 10 times higher than after two primary doses,” said Pfizer.

According to booster shot proponents, antibody counts are sometimes directly linked to the level of protection against SARS-CoV-2. For that reason, they have argued that reductions in antibody counts over time are “likely to be important”.

“The levels of circulating antibodies are likely to be an important part of protection so their waning is likely to be important,” Dr Andrew Hayward, Director of the UCL Institute of Epidemiology and Health Care, told Health Policy Watch

“In many infections, we find a direct relationship between levels of circulating antibody and level of protection which is why some public health bodies measure levels of antibodies in the population to inform vaccination booster programmes.

“There is also some data that suggests higher circulating antibody levels are associated with greater protection across variants, which is an important consideration,” said Hayward, who has tracked how antibody counts change over time.

At the same time, scientists from Pfizer, as well as Hayward, have acknowledged that other components of the immune system – like T cells, B cells, or interferon-gamma – need to be further studied to understand the full breadth of the immune response to vaccines (and to SARS-CoV-2 infection).

“Early protection against COVID-19 without robust serum neutralization indicates that neutralizing titers alone do not appear to explain early BNT162b2-mediated protection from COVID-19,” said a recent study supported by Pfizer. This refers to the fact that people already have some degree of protection against SARS-COV-2 several weeks after their first jab, even though their antibody levels are low at that point.

“Other immune mechanisms (e.g., innate immune responses, CD4+ or CD8+ T-cell responses, B-cell memory responses, antibody-dependent cytotoxicity) may contribute to protection,” the study added.

Known to be a cornerstone of immunity, T cells and interferon gamma are known to be vigorously activated following the Pfizer jab, several studies have revealed.

A marriage between data from the bench and the field 

Going forward, researchers need to marry lab-based data with clinical data from the field to shed light on what is often considered to be the holy grail of immunity: the so-called “correlates of immunity”.

Dr Michael Osterholm, Director of the US Center for Infectious Disease Research and Policy (CIDRAP)

Identification of such correlates would allow scientists to be certain that the metrics they use – like neutralizing antibodies – are an accurate benchmark of the immune response to SARS-CoV-2. 

In addition, such correlates would allow researchers to quickly evaluate how well vaccines are working, for who, and for how long – supercharging COVID-19 R&D and allowing more lives to be saved.

“With regard to what we can say right now about the correlates of protection: they’re clearly inadequate,” said Osterholm. “We don’t know the answers to these questions yet. In the natural history of COVID-19, we are still in the early days.”

“If I had a bag of pixie dust, I would cast it upon the world and marry the immunologic data with data from the field. That will be the ultimate proof of the pudding.”

However, such large-scale studies will take time, he warned. 

“What people have to understand is we’re actually building this plane at 30,000 feet. And that’s hard for people to understand because people want the pandemic to be over.”

Third in a series on COVID-19 booster vaccines. See the second article, COVID Vaccine Boosters in Immuno-compromised People – Could They Also Help Curb Development of New Variants ?

Image Credits: International Monetary Fund/Ernesto Benavides, NIH, CIDRAP.

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