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Uncertainty lingers around long-term immunity from Covid-19 vaccines

Pharmaceutical companies are holding out hope that the mRNA technology used to develop breakthrough Covid-19 vaccines is flexible enough to provide for seasonal shots in case immunity gained from initial vaccination is short-lived.

The first Covid-19 vaccine approved for use in the U.S., Pfizer and BioNTech’s shot was purportedly 95% effective in preventing symptomatic coronavirus infections in a large study group. Positive study results have also been released for Moderna’s vaccine, which secured an emergency use authorization by the Food and Drug Administration on Dec. 18.

The jury is still out on how long the immunity induced by these rapidly developed mRNA vaccines will last.

MRNA vaccines do not trigger immune responses with a weakened or inactive virus as do many traditional viral vaccines. Instead, they send molecular instruction codes – the mRNA – into cells, prompting the cells to produce a protein common to the novel coronavirus. The immune system recognizes the protein as foreign and develops a defense that later goes into action upon encountering the real virus.

Despite the encouraging clinical trial results, Pfizer is being cautious about speculating on the durability of immune response elicited by mRNA vaccines.

“We don’t know how the virus will change, and we also don’t know how durable the protective effect of any vaccination will be,” the company said in a statement.

Pfizer said that if it turns out that the induced immunity lasts only a few months, mRNA vaccines are suitable for repeated administration as booster shots.

If a mutation in the Covid-19 virus affects Pfizer’s vaccine effectiveness, the company said, mRNA technology will enable “rapid development” of adjustments. The technology also allows for a fast production process without the need for complex mammalian cell systems used in traditional vaccine production, the company said.

Hundreds of thousands of people in the U.S. have received Pfizer’s vaccine since the FDA’s Dec. 11 decision to approve its use on an emergency basis. Administration of Moderna’s vaccine to the public began this week.

Multiple other Covid-19 vaccine candidates using a variety of technologies are under development by other large pharmaceutical companies. Viral-vector vaccines, one from Johnson & Johnson, and another from a partnership between AstraZeneca and Oxford University, are in late-stage clinical trials.

Dr. Marc Hellerstein, a biochemistry lab head at the University of California, Berkeley, said researchers will be focused next year on determining which vaccine produces the longest-lived immune response against Covid-19. Of particular importance is the immune response of T cells including CD8+ cells, immune system agents that kill off virus-infected cells in the body, Hellerstein explained.

Studies have found that people infected with SARS-CoV – a similar coronavirus that caused a 2003 outbreak in Asia – had natural T-cell activity that lasted for several years. Levels of antibodies against that virus appear to have been relatively short-lived, however. One study showed that three years after the 2003 outbreak, antibodies were detected in only half of patients. Antibodies work in the extracellular space, finding and neutralizing free-floating viral particles.

“We know that people who recovered from serious betacoronavirus infection, prior to Covid-19, had long-lived T cells and lousy antibody durability,” Hellerstein said of patients’ natural immune response.

Several pharma companies have touted seemingly robust T-cell responses induced by their Covid-19 vaccines. For one, Pfizer’s FDA briefing stated that nearly 90% of study participants who received Pfizer’s vaccine showed CD8+ T-cell production against the targeted coronavirus protein.  

“An important feature of mRNA vaccines is that they stimulate effective T-cell and T-cell memory responses. This ensures longer term protection from viral infection and disease,” Kathrin Jansen, Pfizer’s head of vaccine research, told an FDA advisory panel two weeks ago.

Hellerstein says, however, that more data is needed in order to determine which of the many Covid-19 vaccine options is the real deal as far as inducing strong, long-lasting cell-mediated immunity.

“It’s like having a rookie on a baseball team who is batting well and makes the all-star game. You wouldn’t immediately induct him into the hall of fame,” the researcher said in an interview.

“Of course, this is the greatest public health emergency in recent history. You take what you can get. But this is a real issue. We care about duration of antibodies, but we’d also like to see T cells that are long-lived,” Hellerstein added.

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Moderna’s early clinical trial data indicated that its Covid-19 vaccine induced a T-cell response but that production of CD8+ T cells – the ones that kill off infected cells – was low. Later trial results stated that Moderna’s vaccine was still highly effective at preventing coronavirus infection.

Christian Brechot, a leading virologist and former president of the Pasteur Institute, told Courthouse News that even if Covid-19 vaccines produce short-term immunity, they will help get the outbreak under control. Once the infection rate drops after an initial widespread vaccination, shots can be strategically re-administered to contain outbreaks on a local level.

“Even if we only have six months’ protection, that would be extremely useful to contain the ongoing pandemic. You can you use what we call a ring vaccination. This happened with the Ebola vaccine,” Brechot said. “If you have a cluster, you can vaccinate everybody around an infected individual. And you can curb the epidemic.”

When asked how long mRNA vaccine-induced immunity may last as compared to traditional vaccine immunity, Brechot said, “We simply don’t know.”

He echoed the assertion that mRNA technology can quickly provide new vaccine formulations to address mutations in the coronavirus genome.

“The versatility of the system of developing mRNA vaccines allows us to very rapidly adjust to a new genetic sequence,” Brechot said.

Producers of mRNA vaccines have professed the ability to readily synthesize mRNA formulations to encode countless proteins and thereby custom-tailor immune responses. In a July 2019 presentation, Dave Johnson, a Moderna informatics executive, said that the company had the capacity for monthly production of “up to a thousand unique mRNA [constructs] never before made, ever.”

During a briefing to an FDA advisory committee last week, Moderna researcher Darin Edwards said that the company is monitoring multiple variant strains of Covid-19 and keeping track of mutations by performing deep genetic sequencing in clinical trials.

Covid-19 mutations have come into the spotlight in late December, as British health officials are theorizing that a variant strain in England is causing higher disease transmission rates.

Pfizer is claiming that if vaccine-induced immunity against Covid-19 lasts months rather than years, mRNA vaccines may be more suitable than viral vector vaccines for a regimen of seasonal shots. The company claims that vector vaccines produced by its competitors could elicit what’s called an anti-vector antibody response — which attacks the vaccine particles before they reach their intracellular destination.

The leading Covid-19 vector vaccine candidates are similar to mRNA vaccines in that they are designed to induce immunity by triggering the release of a viral protein inside cells.

One difference is that the vector vaccines use pieces of other viruses, namely adenoviruses, to deliver the payload into a cell, whereas the mRNA vaccines use lipid nanoparticles as the delivery mechanism.  

“Because no viral vector is used, mRNA vaccines pose no risk of an anti-vector neutralizing antibody response, thereby permitting repeated boosting, which may be important if additional vaccinations are recommended in the future,” Pfizer said in a statement.

Prior to the novel coronavirus pandemic, researchers were already developing methods of tweaking viral vectors so that they are less likely to be neutralized by antibodies before they deliver a vaccine payload into cells. Johnson & Johnson and AstraZeneca have not responded to a request for comment on whether their viral vector vaccines against Covid-19 would be suitable for seasonal shots.

Hellerstein said he’s concerned that Covid-19 vaccines that induce only short-term immunity could shake confidence in the public health system and cause some folks to have the mistaken impression they have lasting protection against the virus.

“I can’t imagine the level of disillusionment if people who got vaccinated start to get sick, or their families start to get sick,” Hellerstein said.

He added, “There are going to be pockets where [Covid-19] gets spread. It’s something that’s going to be here with us now. I’m not sure it’s even in the realm of possibility that everybody and their kid is going to get vaccinated every year. And if they don’t, and you don’t have a long-lasting vaccine, I worry.”

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For Hellerstein, the gold standard vaccines impart immunity that lasts for years on end, like shots for yellow fever and polio. Those vaccines use attenuated and inactive viruses, respectively, to induce a full-blown immune defense against multiple viral proteins.

Many leading vaccines for Covid-19, by contrast, focus on a limited range of viral proteins – spike proteins – to trigger an immune defense. Spike proteins line the exterior of coronaviruses, so they are thought to be readily recognized by antibodies on patrol. That makes them an attractive vaccine target, Hellerstein explained.

But Hellerstein said he’s concerned that focusing on spike proteins to elicit an immune response will have drawbacks. The natural T-cell response to the novel coronavirus is more diverse, targeting multiple proteins which leading vaccine candidates do not encode, he said.

Brechot said that in years to come, researchers will be pursuing the development of a vaccine that would be effective against multiple dangerous coronaviruses.

Though the coronavirus family of pathogens are responsible for mild illness like the common cold, particularly virulent strains have emerged in recent years, including SARS-CoV, MERS-CoV and the SARS-CoV-2 strain that is responsible for the current outbreak.

According to Brechot, the speed at which the leading Covid-19 vaccines have been developed is unprecedented.

“What will remain for me as a landmark is the huge effort worldwide, the cooperation, the investment. To develop a vaccine in eight months is incredible,” Brechot said. “It is a breakthrough that demonstrates the capacity of humanity to efficiently fight a new virus.”

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AP Photo/Paul Sancya, Pool

Boxes containing the Moderna Covid-19 vaccine are prepared to be shipped at the McKesson distribution center in Olive Branch, Miss., on Sunday.