New Insights into the SARS-CoV-2 Vaccine

There has been some very interesting news in the last several days that relate to vaccine development. The first of these is a report of results on the Phase 1 trials of the Moderna mRNA vaccine.  Most importantly, the vaccine appeared to be safe; no major adverse events were reported. Vaccines developed binding antibodies to the spike protein of SARS-CoV-2 at levels seen in immunized people, and of those eight who were tested, all had neutralizing antibodies to the virus. This is hopeful; neutralizing antibodies are generally a critical part of a successful immune response. However, researchers measured virus-recognizing antibodies in 25 participants, and detected levels similar to or higher than those found in the blood of people who have recovered from COVID-19. In general, most people who have recovered from COVID-19 without hospitalization do not produce high levels of neutralizing antibodies. Therefore, it is uncertain whether the responses are enough to protect people from infection. In addition, the data of this study has not been published yet. The report also begs the question, what about T cell responses? These will likely be important for long term immunity. he Oxford vaccine, an adenoviral vectored vaccine expressing the spike protein of SARS-CoV-2, wsa also addressed in the previous vaccine post.  In rhesus monkey challenge, a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals. Importantly, vaccinated rhesus macaques were protected from pneumonia without evidence of immune-enhanced disease. However, the scientists found similar levels of viral titers in animals’ noses between unvaccinated and vaccinated groups, probably due to a high dose of challenge virus used in this study.  This has raised a concern whether the vaccination can provide the protection against transmission. The outcome of ongoing clinical trial will provide a better answer whether the vaccine can protect humans from COVID-19.  Eli Lilly is proceeding with a passive immunization trial using monoclonal neutralizing antibodies to SASR-CoV2. It will be interesting to see the results.

Two recent reports (in Cell and MedRxiv) represent an important beginning to answering this question (or questions). In addition to B cells in producing antibodies, T cell can also play a role in preventing infection. Helper T cells activate B cells to secrete antibodies and macrophages to destroy ingested microbes. Cytotoxic T cells kill infected target cells. These two studies  showed, using peptide pools covering predicted epitopes derived from the viral genome, that most convalescent patients had CD4+ and CD8+ responses to a wide variety of viral proteins, including the spike protein. Other common responses include those against the matrix and nucleoprotein as well as nonstructural proteins, such as nsp3 and 4 and ORFs 3a and 8. This suggests that vaccine inducing an immune response to not only the S protein but also these proteins could enhance its protective efficacy. Interestingly, these reports also showed that 40-60% of people who had never been exposed to SARS-CoV-2 also had T cell responses to the virus, and the authors speculated that this could be due to T cell cross-reactivity with the common seasonal cold coronaviruses. This raises some interesting questions. Could previous exposure to cold coronaviruses afford some protection against SARS-CoV2? Do these activities differ in people with severe disease? Is it predictive; that is, could it be a factor in whether infection results in mild or severe disease? How might the presence or absence of these T cell reactivities affect vaccine responses? In any event, it is likely that elicitation of T cell responses will need to be part of a successful vaccine response.

The flip side of T cell responses is that they could be harmful. A cytokine storm has been invoked by many to account for aspects of the end stage disease. If an overactive immune reaction is important, it seems intuitive it should affect younger people disproportionately, as happened in the Spanish flu pandemic. On the other hand, perhaps people with weaker immune systems don’t mount an effective response until late in the disease and generate an inappropriate inflammatory response as a result. A recent report investigated this possibility. The authors looked at moderate, severe and critical patients. They reported a depletion of CD4+ and CD8+ T cells with a CD11a++ memory/effector phenotype, and survival was correlated with recovery of these cells. Conversely, more severe disease was correlated with an increase in S protein-reactive cells producing inflammatory cytokines. Unsurprisingly, with SARS-CoV-2 the immune system appears to be a two-edged sword.

 

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