Sterilizing Immunity and COVID-19 Vaccines

What can we expect from the first-generation vaccines?

News reports that Pfizer's COVID-19 vaccine had an efficacy of over 90% sparked hopes that herd immunity—and ultimately the end of the current pandemic—was not only achievable but closer than many people had imagined This level of efficacy was not only surprising but placed the vaccine alongside those used to prevent once-dreaded diseases like measles, rubella, chickenpox, and polio.

As game-changing as the Pfizer vaccine (and Moderna's equally effective mRNA-1273 vaccine) may be in affording protection against the COVID-19 illness, the results do not reflect complete "sterilizing immunity."

This is the type of immunity that completely prevents a disease-causing pathogen like COVID-19 from establishing an infection. Sterilizing immunity differs from effective immunity in that the latter can prevent illness but still lead to asymptomatic infection.

Sterilizing immunity remains the holy grail of COVID-19 vaccine research, although several candidates in the pipeline show promise. Even so, there are researchers who question whether we actually need a 100% effective vaccine to place COVID-19 behind us and among the likes of polio in the annals of global pandemics.

Unless a vaccine offers sterilizing immunity, there is a chance that the virus can be passed to others even if the infected person has no symptoms.

Close-up of Pfizer/Biotech COVID-19 vaccine in Cardiff, Wales on December 8, 2020
Matthew Horwood / Getty Images

What Is Sterilizing Immunity?

Sterilizing immunity is the best-case scenario for a COVID-19 vaccine and something that is not altogether unimaginable. The vaccines developed for human papillomavirus (HPV), for instance, provide this level of immune protection. The difference, of course, is that HPV is not transmitted via respiratory droplets, and therein lies the central challenge for COVID-19 vaccine developers.

When COVID-19 infection occurs, the virus attaches to a protein called angiotensin-converting enzyme 2 (ACE2) that proliferate in both the upper respiratory tract and lower respiratory tract. This provides the virus the means to hook onto these respiratory tissues and cells and establish an infection.

Although the current vaccine candidates have demonstrated the ability the reduce symptoms and the number of viruses in the lower respiratory tract, there is as of yet no evidence of sterilizing immunity in the upper respiratory tract.

For sterilizing immunity to be achieved, a vaccine needs to trigger a specific immunologic response, typically in the form of neutralizing antibodies (NAb). These are defensive proteins synthesized by the immune system that specifically target and neutralize a disease-causing organism like a virus.

The challenge is that vaccines don't always mount an ample response and/or a specific enough response. Such has been the case with HIV vaccines, which to date have not been able to stimulate the plethora of NAbs needed to neutralize the multitude of genetic subtypes of the virus.

The challenges faced by COVID-19 vaccine developers may not be so daunting. For one thing, COVID-19 does not mutate nearly as quickly as the influenza virus, meaning that the NAbs generated by the first-generation vaccines may offer longer-lasting protection. This, in turn, can reduce the overall rate of spread of the virus, providing it has less opportunity to mutate and create unique strains.

Even so, without a robust frontline defense at the site where COVID-19 enters the body—namely the mucosal tissues of the nose, throat, and upper respiratory tract—a potential for reinfection remains.

Building Immune Memory

When referring to the immune system, you can broadly categorize it in two parts: innate immunity (a generalized frontline defense you are born with) and acquired immunity (in which the immune system launches a targeted response to any foreign agent it encounters).

With acquired immunity, the immune system not only produces antibodies that launch the defense and natural killer (NK) cells that directly attack the foreign agent but also memory cells that remain on sentinel after an infection has been cleared. This immunological "memory" allows the body to mount a rapid response should the foreign agent return.

The question asked by many researchers is how robust and long-lasting the memory response may be with the first-generation COVID-19 vaccines?

Part of the concern arises from the fact that COVID antibody levels tend to wane after infection, suggesting that the protective benefit is limited. This drop is seen especially in people with mild or asymptomatic infection in whom the antibody response tends to be low in the first place.

With that said, the fact that NAb levels drop after an infection is not an uncommon occurrence. It is why people who get the common cold can get easily reinfected in the same season. The difference with COVID-19 is that early studies suggest that memory B cells, a type of immune cell produced by the bone marrow, proliferate even after NAb levels have dropped.

These memory cells sentinel for the virus' return and start churning out "new" NAbs if and when they do. There is growing evidence that the immune system produces an ample supply of memory B cells even in people with mild or asymptomatic disease.

A November 2020 study published in The Cell reported that memory B cells capable of producing COVID-19 NAbs were found in people who experienced mild infection and that their numbers appeared to increase over time.

As such, even if NAbs are decreased, memory B cells may have the ability to quickly replenish levels. This may not fully avert infection but may help reduce the risk of symptomatic infection.

Do We Need Sterilizing Immunity?

When news of waning NAb levels was first reported in the media, many assumed this to mean that immunity was somehow "lost" over time. The assumption was likely premature, in part because there haven't been the waves of COVID reinfections that many had predicted.

With the exception of a Hong Kong man who was found to be infected twice with a different strain of COVID-19, there are few other strongly documented cases. Even in that instance, the man was asymptomatic the second time around, suggesting that the primary infection may have afforded protection against illness.

In the end, no one really knows how many antibodies it takes to defend against COVID-19. Moreover, antibodies, as important as they are, only play a part in the body's overall defense.

Other immune cells, called T cells, are recruited during an infection to seek-and-destroy infected cells or disrupt the virus' ability to replicate. In addition, a subset of T cells, called CD4 helper T cells, are responsible for activating memory B cells should the virus return. These can persist for years.

And, even though their numbers may be small, these CD4 helper T cells still have the ability to launch a robust immune defense. This is evidenced in part by the results of the Moderna vaccine trial.

Clinical studies have shown that the Moderna vaccine provokes a high and sustained NAb response 90 days after the two-dose series. Although the memory response remains unknown, the presence of CD4 helper T cells in study participants suggests that the vaccine may afford longer-lasting protection.

Still, there are many who believe that sterilizing immunity should remain the ultimate goal of vaccine development. They argue that, while the immune response from the Pfizer and Moderna vaccines appears strong, no one really knows for sure how long the response will last.

And, this could be a problem since asymptomatic infections still have the potential to infect others. By contrast, a vaccine that affords complete sterilizing immunity stops infection before it occurs and prevents further spread of the virus.

Progress and Challenges

As millions are slated to be vaccinated with the Pfizer and Moderna vaccines worldwide, increasing focus is being placed on several protein-based COVID-19 vaccines in early phase 2 development.

These protein-based candidates, made from harmless fragments of COVID-19 (called spike proteins), are paired with a secondary agent (called an adjuvant) that activates the immune system.

Although protein-based vaccines take longer to develop than the messenger RNA (mRNA) models employed by Pfizer and Moderna, they have a long history of use and an excellent record for safety and effectiveness. Some have even offered glimpses of complete immunity in early COVID-19 research.

A protein-based vaccine from the manufacturer Novavax was reported to have achieved sterilizing immunity in primates. Subsequent phase 2 trials have shown it to be safe in humans and able to generate a strong NAb response. Further research is needed.

On the downside, vaccines like these are known to stimulate a robust CD4 T cell response but need an adjuvant to render an equally strong NK cell response. It is unclear if the Novavax adjuvant, derived from a plant polysaccharide, will able to deliver the one-two blow needed to achieve sterilizing immunity in humans.

A Word From Verywell

The speed by which the Pfizer and Moderna vaccines have been developed and distributed has been no less than astonishing, and the clinical data thus far has been largely positive.

This shouldn't suggest, however, that it is time to lower your guards when it comes to social distancing and face masks. Until large enough sectors of the population have been vaccinated and further data is returned, it is important to remain vigilant and stick to the public health guidelines.

On the flip side, do not be swayed by the fact that the vaccines are anything less than 100% effective. News reports about waning antibody response neither reflect the complex nature of acquired immunity nor the protective benefit of vaccination even if sterilizing immunity is not achieved.

If concerned about COVID-19 vaccination or simply want more information, call the Department of Health in your state. Many have set up hotlines to answer queries and provide up-to-the-minute information about COVID-19.

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