Protect and Defend

A pair of studies illuminate vaccine promise, immune protection against repeat coronavirus infections

Photoillustration of coronavirus floating around lab equipment with person holding a pipette

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This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

With the global number of confirmed cases at nearly 5 million and more than 300,000 deaths from COVID-19, much remains unknown about SARS-CoV-2, the virus that causes the disease. Two critical questions are whether vaccines will prevent COVID-19 and whether individuals who have recovered from COVID-19 are protected when they encounter the virus again.

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Now, two new studies led by researchers at Harvard Medical School, Beth Israel Deaconess Medical Center and the Massachusetts Consortium on Pathogen Readiness (MassCPR) suggest the answer to these questions appears to be yes, at least in animal models.

Results of these studies published May 20 in Science. “The global COVID-19 pandemic has made the development of a vaccine a top biomedical priority, but very little is currently known about protective immunity to the SARS-CoV-2 virus,” said senior author Dan Barouch, HMS professor of medicine and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess. “In these two studies, we demonstrate in rhesus macaques that prototype vaccines protected against SARS-CoV-2 infection and that SARS-CoV-2 infection protected against reexposure.”

In the first study, the team found that six candidate DNA vaccines—each formulation using a different variant of the key viral protein—induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques. When Chinese scientists released the SARS-CoV-2 genome in mid-January, Barouch and colleagues began working toward a COVID-19 vaccine and have developed a series of candidate DNA vaccines expressing variants of the spike protein, the part used by the virus to invade human cells and a key target for protective antibodies. The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.

To assess the efficacy of the vaccines, the researchers immunized 25 adult rhesus macaques with the investigational vaccines. Ten animals received a sham version as a control group. Vaccinated animals developed neutralizing antibodies against the virus. Three weeks after a booster vaccination, all 35 animals were exposed to the virus.

Follow-up testing revealed dramatically lower viral loads in vaccinated animals, compared with the control group. Eight of the 25 vaccinated animals demonstrated no detectable virus at any point following exposure to the virus, while the other animals showed low levels of virus. Moreover, animals that had higher antibody levels had lower levels of the virus, a finding that suggests neutralizing antibodies may be a reliable marker of protection and may prove useful as a benchmark in clinical testing of SARS-CoV-2 vaccines.

In the second study, the team demonstrated that macaques that recovered from COVID-19 developed natural protective immunity against reinfection with the virus. The results shed much needed light on the critical question of just how much, if any, immunity does infection with SARS-CoV-2 provide against subsequent encounters with the virus.

“Individuals who recover from many viral infections typically develop antibodies that provide protection against reexposure, but not all viruses generate this natural protective immunity,” said Barouch, who is also a co-leader of the vaccine development group of MassCPR and a member of the Ragon Institute of MGH, MIT, and Harvard.

After exposing nine adult macaques to the SARS-CoV-2 virus, the researchers monitored viral levels as the animals recovered. All nine animals recovered and developed antibodies against the virus. More than a month after initial infection, the team reexposed the rhesus macaques to the virus. Upon second exposure, the animals demonstrated near-complete protection against the virus. These data suggest that animals develop natural protective immunity against the virus and the disease that it causes.

Barouch and colleagues are also exploring how infection affects different cell types, with particular focus on immune cells involved in inflammation. To study how immune cells respond to infection and how tissue damage occurs, the team looked at the spread of the virus in individual cells over time, as well as where infected cells are located relative to anatomical landmarks and to each other.

To do so, they used a technique known as cyclic immunofluorescence, developed at the Laboratory of Systems Pharmacology (LSP) at HMS, which allowed researchers to visualize the viral infection in different cell types in intact tissue samples.

"The short-term consequences of SARS-CoV-2 infection in animal models reveal many aspects of COVID-19 that are likely to be relevant to severe disease in humans, including the role of widely disseminated immune response even in regions of the lung with few infected cells,” said study co-author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology in the Blavatnik Institute at HMS and director of the LSP. “These observations show just how damaging this infection can be and lay the foundation for studying COVID-19 in human patients."

These ongoing efforts to profile the behavior of the infection across various cells, tissues and organs can inform the design of therapies and vaccines.

“Our findings increase optimism that the development of COVID-19 vaccines will be possible,” said Barouch. “Further research will be needed to address the important questions about the length of protection as well as the optimal vaccine platforms for SARS-CoV-2 vaccines for humans.”

Future studies will test the Ad26-based vaccines that Barouch is developing in partnership with Johnson & Johnson.

The authors declare no competing financial interests.

These studies were supported by the Ragon Institute of MGH, MIT, and Harvard; Mark and Lisa Schwartz Foundation; Beth Israel Deaconess Medical Center; Massachusetts Consortium on Pathogen Readiness; China Evergrande Group; Bill & Melinda Gates Foundation; Janssen Vaccines & Prevention; the National Institutes of Health (see paper for NIH grant numbers); Burroughs Wellcome Fund Postdoctoral Enrichment Program; Mercatus Center at George Mason University (Fast Grant and Emergent Ventures award).

Adapted from a Beth Israel Deaconess news release.