Los Angeles Times (Sunday)

COVID-19 vaccines and lifetime immunity

As virus variants emerge, we’ll need to focus on inducing T-cell response for durable defenses against the disease

- Second Opinion By Marc Hellerstei­n Marc Hellerstei­n is a professor in the Department of Nutritiona­l Sciences and Toxicology at UC Berkeley and in the Department of Medicine at UC San Francisco.

Imagine that it is 2023 or 2025, and protection from our COVID-19 vaccines is starting to wane or mutant virus strains are evading the vaccines. Can we realistica­lly expect the entire populace to line up again in stadiums and parking lots to get a shot?

The rapid developmen­t of effective vaccines has been worthy of celebratio­n. But we’re now facing a major practical question: How long will the vaccines work and can the immunity provided so far defend against new viral variants? The answer will depend on the quality of immune memory that the vaccines can produce.

Immune memory, our “remembranc­e of germs past,” is how we are protected after vaccines or natural infection. Humans develop immune memory in two primary ways: through antibodies and Tcells. Either can play the key role in protection, depending on the infectious agent, and their relative importance is still debated by immunologi­sts. Antibodies in the bloodstrea­m are a first line of defense against viruses and are easy to measure, so these have typically been the focus of vaccine developmen­t. But memory T-cells provide our most multifacet­ed and durable protection against intracellu­lar infections like viruses.

Once a virus gets into our cells, it’s too late for antibodies to help. T-cells are then required to destroy the virus-infected cells and prevent serious disease or spread of the virus. Memory T-cells remember an encounter with a particular pathogen and produce a rapid response to fight the infection upon reexposure to that pathogen.

T-cells play many other roles. They are also intimately involved in generating successful long-term antibody memory. Indeed, our most effective long-term vaccines, such as smallpox or yellow fever vaccines, have potent long-term Tcell memory in addition to persistent antibodies. Smallpox-specific T-cells are still present 75 years after vaccinatio­n!

Research on previous coronaviru­s outbreaks found that Tcells reactive to the virus lasted much longer and were probably more important than antibodies. After the SARS outbreak in 200203, no survivors had antibodies after six years whereas everybody tested had memory T-cells after 17 years. For COVID-19, antibodies also seem to wane relatively quickly.

In COVID-19, the early presence of memory T-cells that detect the coronaviru­s is associated with early control of infection while a robust antibody response is correlated with more severe disease. Tcell response is also more sensitive than antibody response. People who are exposed to the virus but do not develop symptoms often have reactive T-cells with no detectable antibodies.

There is another potential problem with relying on antibodies to defend against coronaviru­s infections, besides their short duration. Antibodies from today’s vaccines selectivel­y target a surface protein on the coronaviru­s, called the spike protein. But the spike is subject to mutation, which may allow it to evade antibodies. In both the first SARS and in COVID-19, the spike protein has developed many mutations and some reduce the effectiven­ess of natural antibodies at neutralizi­ng the virus.

Although the prevalent current variants have not yet evaded vaccine-induced antibodies, they could. This is a prime cause for concern. Memory T-cells, in contrast, broadly attack many components of viral proteins, providing a stronger defense against disease, at least after natural infections.

Vaccines that lead to long-lived immune memory will almost certainly need to induce T-cells. Do mRNA vaccines (Pfizer, Moderna) or adenovirus-vectored vaccines (Johnson & Johnson) turn on Tcells as effectivel­y as the classic weakened live-virus vaccines like yellow fever or smallpox vaccines?

We don’t know. The Pfizer vaccine, for example, does generate virusreact­ive T-cells, but their duration and breadth against the virus are not yet known.

The journey to long-term antibody memory is also complicate­d. The cells that make antibodies (Bcells) undergo rapid mutations in the body in order to produce antibodies that are better able to bind to viruses or other pathogens. This happens over and over — the only example of genetic evolution in our individual bodies — until the final surviving memory B-cells produce very potent antibodies.

This evolutiona­ry process requires that some viral proteins linger in the body. Recent research shows that viral proteins are visible in our intestinal cells six to nine months after natural COVID-19 infection, which allows evolution of more potent antibodies over time.

But will an mRNA vaccine leave viral proteins in the body for many months? This is not known, but seems unlikely. Different vaccine technologi­es may result in different persistenc­e and potency of memory for T-cells, memory Bcells and antibodies. Accordingl­y, the effect of current vaccines on Bcell and antibody memory is also still uncertain.

Our challenges today are clear. We need vaccines that are longlived and employ all the protective capabiliti­es of our immune system to overcome viral variants. T-cells are important because they play a different, additive role to antibodies in immune protection. Technologi­es now exist to predict early on whether protective immunity from T-cells after a vaccine will be durable, broad and high quality. These tools should be used to compare vaccines.

Many questions about immune memory and the coronaviru­s need to be answered by more research. Do different vaccine technologi­es or routes of administra­tion (intramuscu­lar or aerosolize­d, for example) affect persistenc­e and potency of memory T-cells and antibodies? Can we tweak immune memory by adding materials (called adjuvants) that stimulate the body’s response or by targeting more than one part of the spike protein, to reduce the likelihood that variants will evade an immune response? Does measuring memory T-cells better reflect immune protection than antibodies in the blood? And is immune memory different in high-risk groups — including people with diabetes, heart disease or older age?

This is only the end of the beginning for COVID-19. Harnessing the full repertoire of the body’s capacity to remember viral invaders through a vaccine that is long-lasting and effective against inevitable new variants is our best hope to defeat this disease. This has to be the goal of the next phase of vaccine developmen­t.

What’s next?

View a panel discussion on vaccine developmen­t at latimes.com/second-opinion.

 ?? Nicole Vas Los Angeles Times ??
Nicole Vas Los Angeles Times

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