Vaccine Boosters May Not Always Solve the Mutating Coronavirus Problem

Shin

Humans don’t always win against evolving viruses, but there are reasons to be optimistic

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In 1960, Thomas Francis Jr., MD, a professor of epidemiology at the University of Michigan who was the first to isolate the influenza virus in the U.S., published a paper titled “On the Doctrine of Original Antigenic Sin” in the Proceedings of the American Philosophical Society that is pertinent to our understanding of immunological memory to this day.

Sadly, the concept of original antigenic sin (OAS) has not been given the scrutiny it deserves. But as we face the evolving and mutating severe acute respiratory syndrome coronavirus two (SARS-CoV-2), the thing that causes coronavirus disease 2019 (Covid-19), we must again discuss the OAS.

The original antigenic sin (OAS)

Francis’ paper introduces the antigenic structure, a molecular thing that provokes the immune system to make antibodies to bind and neutralize the antigen. The antigen-antibody products are then disposed of in the spleen and liver. And the immune system forms a memory of the antigen.

This memory enables the immune system to deploy antibodies more quickly and efficiently when it sees the same antigen again. We call this immunity toward a particular antigen, usually of microbial origin. Such immunity can be formed naturally via actual infection or artificially via vaccination.

The spike and nucleocapsid proteins of SARS-CoV-2, for example, are antigens. For the influenza virus, its antigens are the hemagglutinin and neuraminidase proteins.

The crux of the professor’s paper is that antibodies generated for a specific influenza virus strain got deployed again even when the person gets infected with another strain. But different strains of influenza viruses have different antigenic structures, requiring different antibodies to neutralize them. So, those “old” antibodies are ineffective against the newer influenza virus strain. To make matters worse, those “old” antibodies also hinder the formation of updated antibodies and immunological memory.

“The imprint established by the original virus infection governs the antibody response thereafter. This we have called the doctrine of original antigenic sin [OAS],” Francis explained. “The first infection thus governs antibody response to vaccination with other strains [of a particular virus].”

In essence, the immune system insists on doing what it has learned initially, despite that the same trick may not work twice, especially when it comes to virus strains that differ substantially in their antigenic structures.

In OAS, “you preferentially boost what you’ve seen before, at the expense of developing responses to the new stuff,” explained Sarah Cobey, PhD, an associate professor of evolution and ecology at the University of Chicago.

The OAS underpins the grand challenge in creating a reliable influenza vaccine. The seasonal flu shots we rely on to catch up with the rapidly mutating influenza virus are only 40%–60% effective. Although many factors govern such incomplete vaccine efficacy, one of them is the OAS, where prior influenza vaccines sometimes hamper the effectiveness of newer ones. The OAS also occurred with the human papillomavirus (HPV) vaccine, Gardasil. Persons vaccinated with Gardasil mounted poorer immune responses to the updated Gardasil 9 vaccine than those who never received Gardasil.

But it’s not only vaccines. The OAS has also been observed with infectious diseases, such as the influenza virus, human immunodeficiency virus (HIV), Zika virus, dengue virus, Chlamydia trachomatis (bacteria), Leptospirosis species (bacteria), and Plasmodium species (parasites).

The evolving SARS-CoV-2 is resisting vaccines

The mutation rate of SARS-CoV-2 is actually many times slower than other viruses like the influenza virus and HIV (more on this below). But after over a year of widespread transmission, with millions of infected hosts providing opportunities for viral mutations and evolution, multiple strains of SARS-CoV-2 are bound to occur.

Although debatable, the term strain will be used to refer to a variant that has evolved a different biological function. Variants are mutants or genetic variations of a virus that may or may not evolve different biofunction.

In the past few months, we have seen the evolution of many SARS-CoV-2 strains, such as the B.1.1.7 strain in the U.K., B.1.351 in South Africa, P.1 in Brazil, B.1.427/B.1.429 in California, and B.1.617 in India. These strains are causing public health concerns due to their improved abilities at infecting cells, spreading between people, and/or evading antibodies.

Yes, even the ability to escape antibodies. But because vaccines can help our immune system make a huge amount of antibodies, some levels of antibody evasion do not necessarily mean complete vaccine resistance.

For instance, although the antibodies isolated from persons who received the Pfizer-BioNTech or Moderna mRNA vaccine were less effective at neutralizing the B.1.1.7 (the U.K), B.1.351 (South Africa), and P.1 (Brazil) strains, the antibodies still got the job done at clearing the coronavirus. So the mRNA vaccine could still prevent one from contracting Covid-19.

But this is not the case for every vaccine:

  • Antibodies isolated from eight out of 12 (67%) persons who received the Sputnik adenoviral vectored vaccine failed to neutralize or clear the B.1.351 (South Africa) strain.
  • A clinical trial found that the AstraZeneca/Oxford adenoviral vectored vaccine was only 10% effective at preventing Covid-19 caused by the B.1.351 strain. Its efficacy in previous clinical trials was 76%–82%.
  • The efficacy of the Johnson & Johnson adenoviral vectored vaccine has dropped from 72% in the U.S. to 57% in South Africa in a clinical trial.
  • Similarly, the 89% efficacy of the NovaVax protein-based vaccine decreased to 49% in the face of the B.1.351 strain in a clinical trial.

So, SARS-CoV-2 is gradually evolving the ability to evade the immune system and resist certain vaccines. It may just be a matter of time before the most efficacious vaccines get outcompeted by SARS-CoV-2.

This has lead to CEOs of Pfizer, Moderna, and Johnson & Johnson, as well as scientists including Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases and White House chief medical advisor, to suggest that vaccine boosters may be needed to maintain immunity against SARS-CoV-2 in the coming years. It’s still a “may” because nobody knows for sure what sort of SARS-CoV-2 strains will evolve in the future. Still, it’s wiser to be prepared than not.

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What the OAS means for the pandemic

But will vaccine booster shots really solve the problem? Many experts doubt it because of the original antigenic sin (OAS).

“As an immunologist who studies how antibody responses choose their targets, I am concerned that these ‘vaccine updates’ may be less effective in patients that have already received their original shots,” wrote Matthew C. Woodruff, PhD, an immunologist at Emory University. “Immunological memory, the very thing that offers continued protection against a virus long after vaccination, can sometimes negatively interfere with the development of slightly updated immune responses [due to the original antigenic sin].”

We have actually seen signs of the OAS with coronaviruses. Studies have found that SARS-CoV-2 infection and even vaccination could trigger the production of antibodies that target the common cold coronaviruses, which are useless against Covid-19. Whether these “old” antibodies will hamper the formation of immunological memory of SARS-CoV-2 was not studied. But such findings show that ineffective antibodies from prior coronavirus infection can get deployed again for another type of coronavirus.

Although nobody knows with 100% certainty if we will need booster vaccine shots for Covid-19 and if such booster shots will call forth the OAS, we should nevertheless be prepared. We have to ask the right questions now so that the proper research and actions can be taken before it’s too late.

“I do think it’s something that we need to be thinking about,” Michael Worobey, PhD, a professor of ecology and evolutionary biology at the University of Arizona, told STAT in April 2021. “We might actually see lower efficacy five years from now, if people [immune systems] are still locked into recalling the response to the first [SARS-CoV-2] antigen that they saw.”

Thankfully, the relevant research is ongoing. For example, Moderna and the National Institute of Allergy and Infectious Diseases are conducting a clinical trial to investigate how an updated mRNA booster vaccine fares against the B.1.351 (South Africa) strain ill-famed for its antibody evasion ability that has undermined many vaccines (see the above section). Pfizer has also developed an mRNA vaccine that specifically seeks to neutralize the B.1.351 strain, which is currently being tested in clinical trials.

Moving forward, we have at least three ways to prevent the OAS:

  1. Mass vaccination: to limit the number of hosts available for the evolution of SARS-CoV-2. After all, if no new SARS-CoV-2 strains that resist vaccines emerge, there is no need for new booster shots.
  2. Repeat vaccination: to force the immune system to make new, updated memory with multiple booster shots. The idea is to override the OAS influence from the previous immunological memory.
  3. Inventing a universal vaccine: to induce various types of antibodies that can neutralize various strains of SARS-CoV-2. The idea is to create immunological memories of multiple antigens of SARS-CoV-2 at once. A published 2021 study showed that vaccinating mice against eight types of coronaviruses at once generated antibodies that were also effective at neutralizing other coronavirus types not included in the vaccine.

But these methods are still a gamble.

Whether number one is achievable depends on how effectively countries cooperate to distribute vaccines, which is not really working with countries hoarding and embargoing vaccine supplies. The number two method is an arduous one, which plays the long game in catching up with the mutating SARS-CoV-2. In this scenario, vaccine efficacy will vary between seasons, and countries will have trouble vaccinating people from scratch again.

For number three, there’s no guarantee that a universal vaccine will counter the infinite possibilities of virus evolution. The more appropriate term should be “broad-spectrum vaccine.” But at least number three demands lesser vaccine resources and could last for some time, so it’s clearly a better approach than number two and a sensible backup plan if number one fails.

“Rather than playing whack-a-mole with each new problematic variant, it just makes sense to me to use all of our capabilities to really go for a universal SARS-CoV-2 vaccine,” Fauci told The Atlantic. “If we don’t, we’re going to be constantly chasing things, as opposed to getting it off the table.”

Is the OAS a drawback of vaccines? Yes, but it’s more accurate to view it as a downside of immunological memory since it can happen with natural (actual infection) and artificial (vaccine) immunization. So, dodging vaccination is not a solution to the OAS.

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Reasons to be optimistic

Thus far, SARS-CoV-2 follows a convergent evolution pattern. In this type of evolution, different biological entities evolve similar traits to adapt to similar environments. The eyes and wings, for example, evolved convergently in many animal species. The ability to digest lactose (milk sugar) into adulthood has also evolved independently in various human populations.

Although unique mutations are present in some of the SARS-CoV-2 strains, a few mutations — for example, N501Y and E484K — have occurred repeatedly and independently. The N501Y mutation increases the virus’s binding efficiency to the ACE2 receptor on human cells, whereas E484K helps the virus evade antibodies. This observation suggests that SARS-CoV-2 has limited genetic diversity, limiting the number of beneficial mutations it can draw.

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* Source: Rausch et al. (2020). Genetic diversity of the surface glycoprotein of viruses, reflected by their respective sphere length. The numbers 1–5 denote vaccine effectiveness. For example, the mumps vaccine is 88% effective (#2), and the influenza A virus vaccine is 40% effective (#5). There are no effective vaccines for human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV).

Indeed, scientists have described the low genetic diversity of SARS-CoV-2 as its Achilles’ heel, its biggest weakness. Seeing the image above, it’s clear that SARS-CoV-2 has a minuscule genetic diversity than other notorious viruses. Higher genetic diversity means more room to mix and match mutations, which could give rise to numerous strains that are vastly different, and it’s easy for the OAS to occur in such situations. This is why vaccinating for some viruses is more challenging than others. And we can be glad that inventing a vaccine for SARS-CoV-2 is not that challenging.

All in all, although certain vaccines no longer work against some of the SARS-CoV-2 strains, we can still be hopeful that we can win the race against the evolving SARS-CoV-2 (that is not so fast).

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer

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