Researchers at La Jolla Institute for Immunology (LJI) have found that T cells from people who have recovered from COVID-19 or received the Moderna or Pfizer-BioNTech vaccines are still able to recognize several concerning SARS-CoV-2 variants.
Their new study, published online on July 1, 2021 in Cell Reports Medicine, shows that both CD4+ “helper” T cells and CD8+ “killer” T cells can still recognize mutated forms of the virus. This reactivity is key to the body’s complex immune response to the virus, which allows the body to kill infected cells and stop severe infections.
“This study suggests that the impact of mutations found in the variants of concern is limited,” says LJI Professor Alessandro Sette, Dr.Bio.Sci., study senior author and member of the LJI Center for Infectious Disease and Vaccine Research. “We can presume that T cells would still be available as a line of defense against viral infection.”
The researchers emphasize that the study only addresses how the body’s T cells respond to Variants of Concern (VOCs). The researchers emphasize that several of these variants are linked to lower levels of virus-fighting antibodies.
The current study includes data on four of the most prevalent VOCs. Ongoing studies have been expanded to a larger panel of variants, including the Delta (B.1.617.2) variant, which became prevalent after this study had been initiated. The team has also established relationships with more than 20 different laboratories around the world to help monitor T cell reactivity to VOCs.
“These variants are still a concern, but our study shows that even if there is a decrease in antibodies, as other studies have shown, the T cells remain largely unaffected,” says LJI Instructor Alba Grifoni, Ph.D. “The vaccines still work.”
This study was previously published online as a pre-print in March 2021. The findings were then highlighted by National Institutes of Allergy and Infectious Diseases Director Anthony Fauci, M.D., in a March 31 White House press briefing.
“We’re learning more and more that these CD4+ and CD8+ T cells are very important in that they cross-react against certain viral variants,” Fauci said.
In the time since the paper was first published, the researchers have nearly tripled their patient cohort and performed an additional method of stringent statistical analysis. “We’ve also added an unexposed donor cohort,” says study first author Alison Tarke, a Ph.D. student of the University of Genoa, guested in the Sette Lab at LJI.
For the new study, the researchers analyzed T cells from three different groups: People who had recovered from COVID-19, people who had received either the Moderna or Pfizer-BioNTech vaccines, and people never exposed to SARS-CoV-2 (from samples taken before the pandemic).
Both the recovered subjects and the vaccinated subjects were likely to have T cells that recognized the “ancestral lineage” of SARS-CoV-2. This was the original strain that emerged at the beginning of the pandemic; however, the virus has mutated since December 2019, and several variants have been identified as VOCs.
The question was whether people with T cells trained to recognize the ancestral strain would also recognize the new variants. The researchers tested T cell responses from the donor groups against four prominent VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Epsilon (B.1.427/B.1.429).
The researchers found that both vaccinated individuals and the recovered patients had cross-reactive T cells that could target these variants. That is good news for anyone who has received one of the two mRNA vaccines and for anyone who has recovered from any variant of the virus.
“With this study, the underlying message is optimistic,” adds Tarke. “At least, as far as the T cell response goes, your immune system is still able to recognize these new variants and your T cells will be able to respond.”
Similar results reporting largely unaffected T cell reactivity has now been presented through independent studies published in Nature and Science Immunology.
Study co-author and LJI Professor Shane Crotty, Ph.D., says this research highlights the importance of enlisting T cells in fighting SARS-CoV-2.
“COVID vaccines do a fantastic job of making antibodies that stop SARS-CoV-2 infections, but some of the vaccines do less well at stopping infections from variants,” Crotty says. “You can think of T cells as a backup system: If the virus gets past the antibodies—if you have vaccine T cells the T cells can probably still stop the variant coronavirus infection before you get pneumonia.”
Researchers are now looking for ways to take advantage of how flexible the T cells response appears to be. With T cells already working hard to recognize SARS-CoV-2 variants, Grifoni says future “booster” shots could increase immunity by prompting the body to produce more antibodies against the variants and/or by adding additional parts of the virus recognized by T cells.
“T cell epitopes are well conserved among SARS-CoV-2 variants, so incorporating T cell targets into future COVID vaccines could be a clever way to make sure future variants can’t escape the vaccines,” adds Crotty.
There is also the possibility that current SARS-CoV-2 research may one day lead to a universal, “pan-coronavirus” vaccine. This kind of vaccine would train the body to recognize the structural details, such as elements of the spike protein, that all coronaviruses have in common.
“This research shows that a pan-coronavirus vaccine is feasible,” says Grifoni.
The group is now studying a much larger group of 12 different Variants of Concern (VOCs) and Variants of Interest (VOIs), including the Delta variant (B.1.617.2), Eta (B.1.525), Iota (B.1.526), Kappa (B.1.617.1), Lambda (C37) and the variants B.1.526.1, B.1.617.3, R1 and B.1.1.519.
Sette says he’d also like to study T cells from people who have been infected with the variants and see how those T cells react to the ancestral strain of the virus.
Vaccines are the key for preventing the zoonotic virus pandemic caused by SARS-Cov-2 with no specific antidote. Various countries are working to roll out the vaccines.1 , 2 There are four categories of vaccines in clinical trials namely; WHOLE VIRUS, PROTEIN SUBUNIT, VIRAL VECTOR and NUCLEIC ACID (RNA AND DNA). Some of them try to induce the antigen into the body, while others use the body’s own cells to make the viral antigen. Till February 2021, at least seven different vaccines across three different platforms have been rolled out in various countries. Around 100 plus vaccine candidates are in development in different phases.3
Three new clinically important mutant variants of the virus, taking the world by storm have been identified as:
- • The United Kingdom: Identified a London variant called B.1.1.7 (variant VUI-202012/01) with 23 mutations, many of them associated with alterations in a protein made by the virus in the spike protein. Compared to other variants, it spreads more easily and quickly.4 , 5 Experts reported (January 2021) that it may be associated with an increased risk of death compared to other variant viruses, but more studies are needed to confirm this finding. It has been detected in many countries.
- • South Africa: A variant called B.1.351 emerged independently of B.1.1.7. Detected in early October 2020, B.1.351 shares some mutations with B.1.1.7. Many cases were reported from US in January 2021.
- • Brazil: A variant called P.1 emerged among travellers from Brazil, who were tested during routine screening at an airport in Japan, in early January. Variant contains an additional set of mutations that may affect its ability to be recognized by antibodies. This variant was detected in the US in January 2021.
These new variants are capable of spreading faster are emerging and leading to inevitable questions about whether they will make the newly approved vaccines less effective. PCR is the main diagnostic tool which targets 3 parts of the virus to confirm presence of an infection. As per researchers, one target showed repeated negative samples from some parts in England with rapidly rising case numbers, while other two showed positive results.
Scientists found that the virus in these samples had picked up a mutation – a deletion at the same H69 and V70 positions in the protein meaning that PCR was unable to pick the result in some cases. A new lineage of the Covid-19 virus was discovered that had picked up multiple mutations over a relatively short period of time. They designated B117 – the new British Covid-19 variant, also known as VOC 202012/01 which has spread to 50 other countries by mid-January. It is estimated to be 50–75% more transmissible than the original Covid-19 virus.
Other new strains
Other new strains of significance spreading in the US were 20C-US and the CAL.20C in California. There are reports of this variant infecting people who have already been infected with a different variant of the virus last year. One of the mutations carried by CAL.20C, (L452R,) found on the spike protein is being associated with a decreased sensitivity to antibodies, which suggests that it may be able to evade parts of the immune system. Another variant (B1.526) is circulating in New York in February 2021 has also worried scientists.
By mid-February, it accounted for 12.3% of the viruses analysed. It contains two E484K and N501Y, which was also present in variants from Brazil and South Africa. In most cases, treatments and vaccines causes the viruses to evolve and continue spread. Those viruses that resist treatment survive for longer to replicate and spread their genetic material. Hence according to researchers, efforts to spot new variants of Covid-19 as early as possible should include testing sewage samples in cities like Belo Horizonte in Brazil. Hence genome sequencing is the need of the hour.
Another new variant has been located in Finland (Fin-796H) and is reported to have mutations similar to those seen in B.1.1.7 and B.1.351. It also has a mutation in one of the regions (N) recognized by PCR testing. But as per experts, that should not cause a major problem as PCR relies on 2/3 different assays that detect different parts of the virus. Similar issue was seen with in B.1.1.7 variant which escaped the assay that detects the S gene of the virus.6 , 7
In future, corona virus may evade vaccines/treatments
Slow vaccine rollout, mutated strain which is 50% more contagious, may undermine diagnostic testing, antibody treatment and vaccine efficacy. At present the 2 Covid-19 vaccines for use in the US remain highly effective for now. A high level of immunity appears to last for 8 months or more as per research. Researchers around the world agree that the threat of vaccine evading mutations are possible though not necessarily imminent but all also agree that urgent action is required to prevent such a situation. Hence solution is to double down on public health measures to quickly roll out the vaccines.
Increased transmission can increase mutations
The mutated variant that originated in the U.K., called B.1.1.7 allows the spikes on the virus to bind easily with receptors on human cells. B-117 is not a deadly virus, but because of its high infectivity it kills more people than the original strain would have. B-117 has the capability to grow in communities where SARS-CoV-2 is kept under control. Till date the two most notable mutated strains B-117 and 501. V2, from South Africa do not seem to sidestep vaccines or natural immunity. Pfizer announced that a preliminary study finds its vaccine holds up against the B-117 mutations, noting that the nature of the vaccine’s construction should allow adjustments to meet the challenge of corona virus mutations.
One of the major reasons which can give the virus time to mutate its spike protein and escape the vaccine in some countries is the slow vaccine rollout. As per scientists, some vaccines could even start to exacerbate Covid-19 infections via a phenomenon known as antibody dependent enhancement, where certain antibodies end up contributing to the severity of the disease. Vaccine producers like Moderna is developing a booster dose to better tackle emerging SARS-CoV-2 strains. AstraZeneca quoted that in 6–9 months times they may come out with a vaccine for new strains. German biotech Cure Vac recently has collaborated with GlaxoSmithKline to develop messenger RNA (mRNA) vaccines.
The new generation of vaccines for Covid-19 are being given all over the world, but the new strains are a big challenge for them. As per reports, the Oxford vaccine is less effective against a variant common in South Africa than against other strains, causing the country to halt the distribution of that vaccine. A study assessing Israel’s vaccination8 showed that 2 doses of Prizer–Bio Tech vaccine reduces symptomatic cases by 94%, hospital admission by 87% and severe Covid-19 by 92%.As per the article the vaccine was also effective against B.1.1.7. Single dose Covid-19 vaccine made by Johnson and Johnson has been given emergency use authorization US FDA.9
Based on analysis, data on 39,321 adults with no previous signs of infection reported the efficacy as 66.1% for preventing moderate to severe Covid-19, 28 days after vaccination. The company initially reported that the vaccine provided 72% protection against moderate to severe Covid-19 but proportion fell to 66% in Latin America and 57% in South Africa. There is no evidence suggesting vaccines will be any less effective against the new variant. As per experts they are not seeing any increased virulence spike protein, that may reduce vaccine effectiveness so Covid-19 vaccines appears to be adequate in generating an immune response to the variant of the corona virus.
Redesigning of Covid-19 vaccines
The immediate way to combat the threat of emerging variants is probably to quickly vaccinate as many people as possible with current shots. Researchers are of the opinion that new updated vaccines may be required in the future. South African variant called 501Y.V2 (also known as variant B.1.351), is of concern since it carries mutations that sap the potency of virus-inactivating ‘neutralizing antibodies’ that were made by people who received either the Pfizer/Moderna RNA vaccines. It is not clear if these changes are enough to lower the effectiveness of those vaccines.
Other immune responses that vaccines prompt may help to protect against the effects of variants. Data released by Novavax concluded that experimental vaccine, designed to combat the original virus, was 85% effective against a United Kingdom and 50% effective against 501Y.V2. Hence drop in vaccines effectiveness is of high concern. According to the year, the flu vaccine has to be updated as the influenza virus mutates and adapts to escape the immunity already present in the population.
If the corona virus shows similar capabilities, the vaccines may have to regularly updated. Vaccines like Moderna, Pfizer and AstraZeneca instruct cells to produce the virus’s spike protein. Variants including 501Y.V2 carry spike mutations that alter regions targeted by neutralizing antibodies. Another possibility is to change older versions identified in Wuhan, China for an updated molecule with specific amino-acid changes that hinder antibody responses. It also needs to be determined whether any such changes would have knock-on effects that alter how the immune system reacts to the vaccine. Other options is to include both new and old forms of the spike protein in a single jab (multivalent vaccine).
Universal Covid-19 vaccine
Solution is to develop a universal vaccine that is future-proof against the evolving corona virus. Clue lies in examining vaccines for other viral infections that have stayed effective for decades. Yellow fever has a weakened form of yellow fever virus. Just like Covid-19, yellow fever is caused by an RNA virus. As per research, T cells largely ignore the surface antigens of the yellow fever virus. Instead, they recognize antigens within the virus.
Influenza viruses mutate faster than Corona virus. They have a step in their replication process that proofreads the copied genetic code for errors, slowing the introduction of mutations. All depends on how quickly we can get the pandemic under control. The likelihood of mutations depends on how much virus is circulating,10 , 11 It is uncertain, how long immunity from the Covid-19 vaccine will last. A flu vaccine is needed every year not only because the flu virus mutates quickly but also because the antibody response wanes over time.12
The present Covid-19 vaccines are expected to provide some protection against new virus variants, because they elicit a broad immune response. Hence changes/mutations in the virus should not make vaccines completely ineffective. If these vaccines prove to be less effective against one or more variants, it will be possible to change the composition of the vaccines to protect against these variants hence, in future vaccines may need to incorporate more than one strain when in development or booster shots may be required.
Stopping Measures to reduce transmission including frequent hand washing, wearing a mask, physical distancing, good ventilation and avoiding crowded places or closed settings continue to work against new variants by reducing viral transmission thereby also reducing opportunities for the virus to mutate. High-risk groups have to be prioritized to maximize global protection against new variants and minimize the risk of transmission. Ensuring equitable access to Covid-19 vaccines is more critical than ever to address the evolving pandemic.
People’s future response to revaccination with the updated vaccine
As per research, people tend to have more robust immune responses to the first variant of a pathogen that they encounter than subsequent variants. Hence updated vaccines may trigger lower immune responses as compared to the first one. As per evidence, RNA vaccines may not fall prey to this trend. But some RNA vaccines trigger surprisingly complex immune responses, yielding antibodies that target regions of viral proteins that are often not detected in responses to other kinds of vaccines which means that RNA vaccines will also be better able to target the changes present in a variant. Many US companies are planning to update their vaccines in the near future.
A French company is working on an inactivated vaccine using the complete virus, to potentially form a response to all possible epitopes, a term for the portions of the virus’s proteins that the immune system can recognize. It also combines the inactivated virus with an adjuvant. As more people get vaccinated, it is expected that the virus circulation should decrease, which will further lead to fewer mutations.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035083/
More information: Cell Reports Medicine (2021). DOI: 10.1016/j.xcrm.2021.100355 , www.cell.com/cell-reports-medi … 2666-3791(21)00204-4