Researchers define immune determinants of protection against SARS-CoV-2 in mice

Researchers in the United States have conducted a preclinical study defining the roles that different arms of the immune system play in fighting primary infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as reinfection and infection following SARS-CoV-2 vaccination.

The novel SARS-CoV-2 virus is the agent responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic that has now caused more than 3.42 million deaths globally.

“While effective vaccines are currently being rolled-out in many countries, the adaptive immune determinants that promote viral clearance and confer protection remain poorly defined,” said the researchers.

Now, the Yale University School of Medicine team has shown that, in mice, both humoral (antibody) and cellular adaptive immunity contributed to viral clearance following primary infection.

However, while T cells played an important role in clearing primary infection, they were not required for protection against infection in convalescent or vaccinated mice.

Reassuringly, both the convalescent and vaccinated mice were not only protected against infection with the original Wuhan-1 strain of SARS-CoV-2, but also the B.1.351 variant of concern that emerged in South Africa.

“These results highlight the in vivo protective capacity of antibodies generated by both vaccine and natural infection,” writes Akiko Iwasaki and colleagues.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

The relative contributions of cellular and humoral immunity remain poorly defined

The development of adaptive immune responses to both SARS-CoV-2 infection and vaccination has been well characterized. Preclinical studies have also shown that infection- or vaccine-induced immunity is sufficient to protect against reinfection with the original strain of SARS-CoV-2.

“However, few of these studies have identified the essential correlates of protective adaptive immunity,” say the researchers.

The relative contributions of cellular and humoral immunity in viral clearance and protection against reinfection remain poorly defined in the case of both vaccine-induced and infection-induced immunity.

Furthermore, “questions regarding the degree to which T cell-mediated immune memory may compensate for waning antibody mediated immunity have become even more critical given the emergence of viral variants of concern that evade neutralizing antibody responses from both vaccinated and convalescent individuals,” adds the team.

What did the researchers do?

The researchers used a mouse model of SARS-CoV-2 that employs transduction of the respiratory tract with adeno-associated virus (AAV) expressing human angiotensin-converting enzyme 2 (hACE2) to explore the immunological determinants of protection from infection. The hACE2 receptor is the host cell structure SARS-CoV-2 binds to as the initial stage of the infection process.

Using this AAV-hACE2 model, the researchers could infect mice of different genetic makeups to identify how deficiencies in certain components of the adaptive immune system affect the clearance of and protection from SARS-CoV-2.

First, to assess whether adaptive immunity is required to clear the primary infection, the team infected  AAVhACE2 Rag1-/- mice – which do not produce mature B or T cells – with the original SARS-CoV-2 strain that emerged in Wuhan (Wuhan-1 or WA1).

These mice were unable to clear the virus, with stable levels of viral RNA and infectious virus maintained in lung tissue for more than 14 days post-infection. Wildtype mice, on the other hand, had cleared the virus at seven days post-infection.

“These data confirm that in the absence of adaptive immunity, innate immune responses are insufficient to clear acute SARS-CoV-2 infection,” says Iwasaki and colleagues.

Cellular and humoral immunity contribute to clearance of primary infection

Next, to assess the requirement of humoral immunity in viral clearance, the researchers infected AAV-hACE2 µMT mice - which are deficient in B lymphocytes - with the WA1 strain.

These mice retained the ability to clear the virus, although more slowly than in wild-type mice.

“These results suggest that cellular immunity is sufficient for viral clearance in the setting of acute infection, even in the absence of humoral responses; however, humoral immunity is not completely redundant in its contribution to viral clearance,” says the team.

Next, the researchers investigated the protective role of T cell-mediated versus antibody-mediated immunity by transferring either T cells or sera from convalescent mice to wild-type mice that were then infected with SARS-CoV-2.

While convalescent T cell transfer resulted in a detectable reduction of viral RNA and titers in the lung at seven days post-infection, the transfer of convalescent sera (containing antibodies) completely reduced the infectious viral load.

The role of humoral and cellular immunity in vaccinated and convalescent mice

Finally, the team assessed the role that humoral and cellular immunity played in both vaccinated and convalescent mice in protecting against homologous viral challenge and challenge with the B.1.351 variant.

The B.1.351 lineage has previously been shown to exhibit resistance to neutralizing antibody activity in convalescent and vaccinated sera.

The researchers found that CD8 memory T cells were not required to confer significant protective immunity in the lower respiratory tract in either the convalescent or the vaccinated animals.

“These data support antibody responses as the key determinant of protection against SARS-CoV-2 reinfection, with CD8+ memory T cells playing only a supporting role,” says Iwasaki and colleagues.

Furthermore, the team found that while there was some loss of protection against the B.1.351 lineage in vaccinated or convalescent mice, humoral immunity was still sufficient to completely prevent disease.

What are the implications of the study?

“While T cells were important in the clearance of primary infection, they were not required for protection against reinfection or vaccine-mediated protection,” say the researchers.

Iwasaki and colleagues say the results are reassuring since they indicate that a robust humoral immune response is sufficient, even in the setting of decreased neutralizing capacity.

“These results also have important public health and vaccine development implications, as they suggest that antibody-mediated immunity may be a sufficient correlate of protection,” concludes the team.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.


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