Look beyond antibodies against T cells for effective COVID vaccines

More than 100 companies are rushing to develop a vaccine against COVID-19 as the U.S. government is promoting vaccine rollouts at “warp speed”, perhaps by the end of the year, but effective and long-lasting vaccines It’s too low and potentially dangerous, according to Mark Hellerstein, a distant University of California, Berkeley.

Most vaccine developers are aiming for strong antibodies response It focuses on a single protein, called the spike protein, that neutralizes the virus and acts as an immune antigen. Still, compelling evidence points to problems with both of these approaches, says UC Berkeley professor Heller Stein of nutrition and toxicology.

A better strategy is to take lessons from one of the world’s best vaccines, the 82-year-old yellow fever vaccine. This vaccine stimulates a long-lasting protective T cell response. T cells Immune cells We have been monitoring our body continuously for decades and are ready to react quickly if the yellow fever virus is detected again.

“We know what a really good vaccine looks like Virus infection“Hellerstein said. “During the phase II trial, we were able to examine not only the detailed response of T antibody, And correlate these responses with who did or didn’t do it in the next few months. And I think we have a good understanding of the laboratory characteristics of vaccines that work. Then you should be able to choose the good one.”

To determine whether a particular vaccine provides long-lasting cells and a durable T-cell mediated using Hellerstein’s laboratory technology developed and completed over the last 20 years to assess T cell longevity. It is now possible to tell within 3 or 4 months protection.

Hellerstein presented his discussion today in a review article published in The Vaccine magazine.

“There isn’t much room for big error here,” said Hellerstein. “We can’t go beyond head even on suboptimal or dangerous roads. The last thing we want is that immunized people get sick in a few months or a year.” Or they will get sicker than they have, or the approval of a vaccine trial has the obligation to ensure that the quality and durability of the T cell response is confirmed, which does not delay the licensing process .”

Misguided focus on antibodies

Hellerstein points out that the antibody is not the major protective response against infection by a family of viruses, including the coronavirus, SARS-CoV-2. In fact, high levels of antibodies to these viruses exacerbate the symptoms of the disease, and antibodies to coronaviruses, including SARS-CoV-2, do not appear to last too long.

This was seen in people infected with the first SARS virus, SARS-CoV-1, in 2003. SARS patients who died subsequently had higher levels of antibodies during acute infection and worse clinical lung injury than those who recovered SARS. In MERS, which is also a coronavirus infection, survivors with high antibody levels spent longer in the intensive care unit and needed ventilator support compared to subjects without detectable antibodies.

In contrast, strong T cell levels in SARS and MERS patients correlated with better outcomes. So far, the same has been done for COVID-19 patients.

“A strong antibody response correlates with more severe clinical disease of COVID-19, whereas a strong T cell response correlates with less severe disease. Also, compared to virus-reactive T cells in recuperated SARS patients. And antibodies are short-lived,” Hellerstein said.

The most worrisome part he said is that antibodies can exacerbate subsequent infections, causing so-called antibody-dependent potentiation. Two vaccines, one against cat coronavirus and the other against dengue, a flavivirus that affects humans, can cause fatal reactions by the antibodies they elicit. , Had to cancel. If the antibody binds weakly to these viruses or falls to low levels, it may fail to “neutralize” the virus, but instead help it get into the cell.

Antibody-dependent enhancement is well known in diseases such as dengue fever and deer. A recent study at the University of California, Berkeley in Nicaragua shows that antibodies produced after Zika infection can cause serious illness such as deadly hemorrhagic fever after being infected with the related viral dengue fever. It was shown that there is a nature. This dangerous cross-reactivity also occurs with antibodies produced by the vaccine. Hellerstein pointed out that a strong T cell response is the key to maintaining high levels of antibodies and may prevent or counteract the antibody-dependent potentiation.

T cells are a long-lasting defense

Hellerstein mainly studies the dynamics of metabolic systems, tags body proteins and cells with hydrogen, deuterium non-radioactive isotopes, and tracks them throughout the organism. Using advanced mass spectrometric techniques designed by his lab, he began studying T cell birth and mortality in HIV / AIDS patients over 20 years ago.

Three years ago, he teamed up with immunologist Rafi Ahmed and his colleagues at Emory University to find out how many yellow fever-induced T cells stay in the blood. Surprisingly, the same T cells that were created to attack the yellow fever virus in the first few weeks after live virus vaccination were still present in the blood, responded to the virus several years later, and had a longevity. Has been found to be significantly longer. He and his team estimated that anti-yellow fever T cells lasted at least 10 years, perhaps longer, providing lasting protection from just one shot. Their long life span allows these cells to develop into unique types of protective immune cells.

“They are T-cells, a kind of adult stem cells, that have been sitting quietly in very few for years or decades, but when they see viral antigens, they become wild and divide like crazy. It releases cytokines and does other useful things to neutralize the virus,” he said. “They are like skilled old soldiers resting quietly in the fields, ready to explode on the first signs of trouble.”

The same deuterium labeling technique can be used to measure the persistence of the T cell response of the COVID-19 vaccine, helping to identify the best vaccine candidate during the course of the trial.

“I can tell you the quality and durability or longevity of your T cell response within a few months, in my view,” he said. “These tests can be used to determine vaccines: do candidate vaccines reproduce the benchmarks found in highly effective vaccines, such as those against smallpox and yellow fever?”

Hellerstein said he was motivated to write a review of the role of antibodies and T cells in protective immunity against SARS-Cov-2. Vaccine development The company is probably not interested in testing more than antibody responses. The reason given is that it could slow down the approval process or even cause vaccine problems.

“That’s why I wrote this review honestly, because I was so upset by this reaction,” he said. “At this moment in history, don’t you want to know something that might help us? We need to look beyond the narrow focus on antibodies to look at T cell width and endurance.”

Focus on spike proteins

Hellerstein was also surprised that most vaccines in development focus solely on inducing an antibody response to only one protein or antigen of the COVID-19 virus. Virus Unlock the door to the cell. However, significant new research has shown that natural infection with SARS-CoV-2 stimulates a wide range of T cell responses to several viral proteins, as well as spike proteins.

He said that T cells produced after natural infection of SARS patients are also very long-lived. According to a recent study, patients who recovered from SARS-CoV-1 infection in 2003 produced CD4 and CD8 T cells that were still present after 17 years. These T cells also respond to today’s SARS-CoV-2 proteins. This indicates that T cells cross-react to a variety of coronaviruses, including those that cause the common cold, since the patient has never been exposed.

All of these findings do not limit the vaccine to one protein, rather than the complement of viral proteins that the body exposes to the body during natural infections, rather than the widespread persistence of T cells found after natural infections. It asks whether to induce protection. ..

In contrast, vaccines such as the yellow fever vaccine that use an attenuated virus (a virus that divides, but fails to function and does not harm the body) tend to generate a strong and long-lasting broad immune response. ..

“When approving a vaccine based on laboratory markers, the key question is, “What is the relationship with protective immunity?” In my view, T cells are much better correlated than antibodies with protective immunity to coronavirus Coronavirus.. Also, T cells do not show the same results in COVID-19 as the antibody-dependent potentiation that could make things worse.”

He warned that the effectiveness and durability of the first COVID-19 vaccine could affect the public’s already skeptical attitude to the vaccine for many years.

“It’s a nightmare of public health and’trust in health care’ and can spread over the years.vaccine Forces-when immune defenses decline or antibody-dependent enhancement occurs and face the threat of recurrent COVID-19 among immunized people,” he wrote in his review article.