Researchers Find Potential Path to a Broadly Protective COVID-19 Vaccine Using T Cells

Rachel Leeson wrote . . . . . . . . .

Gaurav Gaiha, MD, DPhil, a member of the Ragon Institute of MGH, MIT and Harvard, studies HIV, one of the fastest-mutating viruses known to humankind. But HIV’s ability to mutate isn’t unique among RNA viruses — most viruses develop mutations, or changes in their genetic code, over time. If a virus is disease-causing, the right mutation can allow the virus to escape the immune response by changing the viral pieces the immune system uses to recognize the virus as a threat, pieces scientists call epitopes.

To combat HIV’s high rate of mutation, Gaiha and Elizabeth Rossin, MD, PhD, a Retina Fellow at Massachusetts Eye and Ear, a member of Mass General Brigham, developed an approach known as structure-based network analysis. With this, they can identify viral pieces that are constrained, or restricted, from mutation. Changes in mutationally constrained epitopes are rare, as they can cause the virus to lose its ability to infect and replicate, essentially rendering it unable to propagate itself.

When the pandemic began, Gaiha immediately recognized an opportunity to apply the principles of HIV structure-based network analysis to SARS-CoV-2, the virus that causes COVID-19. He and his team reasoned that the virus would likely mutate, potentially in ways that would allow it to escape both natural and vaccine-induced immunity. Using this approach, the team identified mutationally constrained SARS-CoV-2 epitopes that can be recognized by immune cells known as T cells. These epitopes could then be used in a vaccine to train T cells, providing protective immunity. Recently published in Cell, this work highlights the possibility of a T cell vaccine which could offer broad protection against new and emerging variants of SARS-CoV-2 and other SARS-like coronaviruses.

From the earliest stages of the COVID-19 pandemic, the team knew it was imperative to prepare against potential future mutations. Other labs already had published the protein structures (blueprints) of roughly 40% of the SARS-CoV-2 virus, and studies indicated that patients with a robust T cell response, specifically a CD8+ T cell response, were more likely to survive COVID-19 infection.

Gaiha’s team knew these insights could be combined with their unique approach: the network analysis platform to identify mutationally constrained epitopes and an assay they had just developed, a report on which is currently in press at Cell Reports, to identify epitopes that were successfully targeted by CD8+ T cells in HIV-infected individuals. Applying these advances to the SARS-CoV-2 virus, they identified 311 highly networked epitopes in SARS-CoV-2 likely to be both mutationally constrained and recognized by CD8+ T cells.

“These highly networked viral epitopes are connected to many other viral parts, which likely provides a form of stability to the virus,” says Anusha Nathan, a medical student in the Harvard-MIT Health Sciences and Technology program and co–first author of the study. “Therefore, the virus is unlikely to tolerate any structural changes in these highly networked areas, making them resistant to mutations.”

You can think of a virus’s structure like the design of a house, explains Nathan. The stability of a house depends on a few vital elements, like support beams and a foundation, which connect to and support the rest of the house’s structure. It is therefore possible to change the shape or size of features like doors and windows without endangering the house itself. Changes to structural elements, like support beams, however, are far riskier. In biological terms, these support beams would be mutationally constrained — any significant changes to size or shape would risk the structural integrity of the house and could easily lead to its collapse.

Highly networked epitopes in a virus function as support beams, connecting to many other parts of the virus. Mutations in such epitopes can risk the virus’s ability to infect, replicate, and ultimately survive. These highly networked epitopes, therefore, are often identical, or nearly identical, across different viral variants and even across closely related viruses in the same family, making them an ideal vaccine target.

The team studied the identified 311 epitopes to find which were both present in large amounts and likely to be recognized by the vast majority of human immune systems. They ended up with 53 epitopes, each of which represents a potential target for a broadly protective T cell vaccine. Since patients who have recovered from COVID-19 infection have a T cell response, the team was able to verify their work by seeing if their epitopes were the same as ones that had provoked a T cell response in patients who had recovered from COVID-19. Half of the recovered COVID-19 patients studied had T cell responses to highly networked epitopes identified by the research team. This confirmed that the epitopes identified were capable of inducing an immune reaction, making them promising candidates for use in vaccines.

“A T cell vaccine that effectively targets these highly networked epitopes,” says Rossin, who is also a co–first author of the study, “would potentially be able to provide long-lasting protection against multiple variants of SARS-CoV-2, including future variants.”

By this time, it was February 2021, more than a year into the pandemic, and new variants of concern were showing up across the globe. If the team’s predictions about SARS-CoV-2 were correct, these variants of concerns should have had little to no mutations in the highly networked epitopes they had identified.

The team obtained sequences from the newly circulating B.1.1.7 Alpha, B.1.351 Beta, P1 Gamma, and B.1.617.2 Delta SARS-CoV-2 variants of concern. They compared these sequences with the original SARS-CoV-2 genome, cross-checking the genetic changes against their highly networked epitopes. Remarkably, of all the mutations they identified, only three mutations were found to affect highly networked epitopes sequences, and none of the changes affected the ability of these epitopes to interact with the immune system.

“Initially, it was all prediction,” says Gaiha, an investigator in the MGH Division of Gastroenterology and senior author of the study. “But when we compared our network scores with sequences from the variants of concern and the composite of circulating variants, it was like nature was confirming our predictions.”

In the same time period, mRNA vaccines were being deployed and immune responses to those vaccines were being studied. While the vaccines induce a strong and effective antibody response, Gaiha’s group determined they had a much smaller T cell response against highly networked epitopes compared to patients who had recovered from COVID-19 infections.

While the current vaccines provide strong protection against COVID-19, Gaiha explains, it’s unclear if they will continue to provide equally strong protection as more and more variants of concern begin to circulate. This study, however, shows that it may be possible to develop a broadly protective T cell vaccine that can protect against the variants of concern, such as the Delta variant, and potentially even extend protection to future SARS-CoV-2 variants and similar coronaviruses that may emerge.

Source: Massachusetts General Hospital

What’s for Lunch?

Grilled Salmon Set Meal at Sakanaya in Kyoto, Japan

The price is 880 Yen plus tax.

Some Myeloma Patients Get No Protection From COVID-19 Vaccines

Cara Murez and Ernie Mundell wrote . . . . . . . . .

Because they’re often given drugs that suppress their immune systems, people battling a blood cancer known as multiple myeloma have varying responses to the COVID-19 vaccine, new research shows.

Some patients had no evidence at all of COVID-fighting antibody production after getting two doses of vaccine, the new study found.

In a minority of cases, fully vaccinated myeloma patients went on to develop sometimes serious cases of COVID-19, according to the team of New York City researchers.

All of this “underscores the need for routine blood tests on multiple myeloma patients after vaccination to understand their risk and potential need to continue wearing masks and socially distance until the pandemic wanes,” said study co-lead author Dr. Samir Parekh. He directs translational research in multiple myeloma at The Tisch Cancer Institute at Mount Sinai.

In the study, the Mount Sinai team analyzed the antibody levels of 320 multiple myeloma patients, including 260 patients who received two doses of COVID-19 vaccinations (either Pfizer-BioNTech or Moderna). The researchers reported that about one in every six patients (about 16%) had undetectable antibodies to SARS-CoV-2.

Multiple myeloma patients who had experienced a prior infection with the COVID-19 virus before their vaccination showed immune responses that were 10 times higher than those who had not, the team noted in a Mount Sinai news release.

In addition, about 10 study participants who received at least one dose of COVID-19 vaccine did develop the illness during the study period, the findings showed. In four cases, the illness was so severe that patients needed to be hospitalized, and one patient died.

The researchers repeated antibody measurements from before patients’ first vaccine dose until 60 days after the second vaccination. These typically showed delayed and suboptimal responses, according to the study, particularly in patients with multiple myeloma who had not contracted COVID-19 before their vaccinations.

Cancer treatment status seemed to matter, too: Patients on active cancer treatment had significantly lower antibody levels after two vaccine doses compared to those who weren’t being treated at the time of vaccination, the researchers said.

The new data “also calls for clinical trials to study the use of prophylactic therapies, like monoclonal antibodies, to mitigate COVID-19 risk or use of different vaccines or booster vaccinations in these patients,” said Parekh, who is also professor of medicine (hematology and medical oncology) at the Icahn School of Medicine at Mount Sinai in New York City.

Study co-lead author Dr. Ania Wajnberg is director of clinical antibody testing at The Mount Sinai Hospital. “As we continue to reopen the country, it is important for people with immune system disorders, including multiple myeloma, to work with their doctors and to understand their response to their COVID-19 vaccines due to the varied antibody responses to the vaccines we see in this study,” Wajnberg said in the news release.

Speaking in an interview with HealthDay Now, Dr. Joshua Richter, assistant professor of medicine at Tisch, said that, in general, blood cancer patients “don’t have the same robustness of their protection as people without hematological malignancies.”

Richter, who wasn’t involved in the new study, stressed that the human immune system has many components, and the immune response to COVID-19 vaccines for these patients is not an “all or none” situation.

“A lot of people are measuring their antibody levels, which kind of shows their [immune system] B-cell response,” Richter explained. “Some of the researchers at my institution are actually doing studies looking into the T-cell response. So even those people that show no antibody production may still have some protection against COVID.”

There might also be ways to “bump up” the immune response to vaccination, he noted.

“One of them may be giving them an extra dose of the vaccine, like a booster. There’s some recent data presented for solid organ transplant recipients [who also take immune-lowering drugs] about how they’ve been benefiting from that strategy,” Richter said.

“Another strategy that’s under investigation is using some of the commercially available antibody drugs to treat COVID, like the Regeneron drug, which may be worthwhile to give to some of these patients to provide extra protection against COVID,” Richter added.

The study authors said they are continuing to study the response of myeloma patients to COVID-19 vaccines. They believe that patients who mount low-to-modest antibody responses may lose protection more rapidly than those who mount a high response.

The findings were published online in Cancer Cell. They may be relevant to other cancer patients undergoing treatment and to immunocompromised patients, the researchers said.

Source: HealthDay

Broiled Fish Marinated with Miso

Ingredients

2 marlin (kajiki) steaks, about 10 oz
1/8 tsp salt
1/2 lemon

Miso Marinade

14 oz white miso
3 tbsp mirin (sweet rice wine)
2 tbsp rice wine
2 tbsp sugar

Method

  1. Wash the fish. Cure in salt for 30 minutes.
  2. Wash the salt off the fish, then sprinkle 1 tablespoon rice wine over the fish. Wipe dry.
  3. Mix marinade ingredients in a bowl.
  4. Wrap fish in one layer of white cheesecloth.
  5. Place fish in the bowl of marinade and set aside in the fridge overnight.
  6. When ready to cook, take fish from fridge and remove the cheesecloth. Rinse and wipe dry.
  7. Broil in the oven under medium heat (350° to 400°F) until done, about five minutes.
  8. Squeeze on some lemon juice before serving.

Makes 2 servings.

Source: Japanese Cuisine