Immunology of acute COVID and vaccine responses

When SARS-CoV-2 began to emerge, researchers and medical professionals have scrambled to piece together the evolving immunopathology of the virus behind what is now a global health pandemic. The Iwasaki Lab is part of this ongoing effort to develop a clearer picture of how COVID-19 breaks into us and the various immune responses that it initiates. Here’s what we have found and what we are working on:

Among COVID-19’s most serious complications is pneumonia, a condition where virus-mediated inflammation of air sacs in our lungs causes buildup of fluid. The pathogenesis of this coronavirus-induced pneumonia likely occurs in two phases: a viral phase, where virus replication and entry into cells causes direct damage to tissues, and a dependent second stage where our own body’s recruitment of immune cells to fight the virus can cause both localized and systemic inflammation. Pulmonary diseases can at least partially be attributed to excessive vascular permeability, disturbing the ability of blood vessels to regulate macromolecule exchange across its epithelial walls — while the extrapulmonary illnesses of some COVID-19 cases seem to be multi-dimensional in causation. Researchers currently point to tissue, vascular, and neuronal damage; gut dysbiosis; and cytokine release as potential reasons.

But what is so different about this virus, and our immune response to it, that let this happen? In a March 2022 paper published in Science, immunologists including Prof. Iwasaki summarize current hypotheses behind disease pathogenesis.

First, delayed immune responses. Some patients with severe COVID-19 are unable to efficiently produce the interferons necessary for antiviral immunity — while others have autoantibodies against certain interferons, a characteristic that seems to become more frequent with age. Defects in innate immunity will enable uncontrolled virus replication and pathology. In addition, delayed adaptive immunity caused by ineffective innate immunity, lymphopenia, T-cell apoptosis, plasmablast expansion, and excessive cytokine release, may also contribute to disease severity and progression. Our work showed that delay in neutralizing antibodies correlated with mortality in COVID patients.

Second — and ironically — our body’s overactivated immune response, incited by infection, can cause more damage and inflammation than the virus itself. While certain macrophages and immune cells deplete in population from pathogenic autoantibodies, some myeloid cells can continue to circulate in high numbers without regulation, producing inflammatory molecules and causing tissue damage. This inflammation, in tandem with viral damage, can then disturb vascular structure to the point of allowing excessive blood clots and dangerously increasing permeability. We have demonstrated that late phase interferon responses contribute and correlate with disease pathology in both mouse model of COVID and in patients. In addition to the misfiring of immune responses, in collaboration with Dr. Aaron Ring’s lab, we found diverse functional autoantibodies that impair immune clearance of the virus, as well as target host tissues that could lead to tissue damage.

Notably, host demographics influence the outcome of COVID. Male sex is a risk factor for severe and lethal COVID, as well as older age. We found that early immune responses differ between male and female hospitalized patients, and that such differences may lead to severe outcomes. For more, read our review on this topic here. In addition, we examined the impact of COVID-19 in pregnant women. Even without the direct infection of placenta, we found profound transcriptional changes in people who became infected with SARS-CoV-2 during pregnancy. These changes may result in impact on fetal development in utero, as we have demonstrated for Zika virus infection.

Our body’s experience in recognizing, combating, and remembering pathogens via its immune system confers natural immunity — it is why we have a window of “protection” from the COVID-19 virus after previously grappling with it. However, this incurs costs to the host, in the form of both acute and long COVID. A different type of immunity is vaccine-induced immunity, where an individual is given vaccines to generate immune responses without becoming infected with the pathogen. Based on these “instructions,” the body then makes proteins and antibodies against the specific genetic and structural information of the virus, so that it knows how to protect itself from the pathogen upon future encounters.

A remarkable achievement during COVID-19 pandemic is the development and implementation of safe and effective vaccines. Within a year of viral outbreak, vaccines were developed and deployed to protect human populations.

Unfortunately, like many other viruses, SARS-CoV-2 continuously adapts and evolves amid pressure to survive and replicate, resulting in mutated strains or the variants of concern (VOC), that are not only more transmissible, but also can evade the antibodies we have acquired from previous vaccinations. Vaccines can wane in efficacy over time, and to tackle emergent variants, many companies are working on cloning variant sequences and spike proteins — and incorporating that information into new versions of vaccines that can then be used as a booster shot. We have compared the ability of mRNA vaccines to elicit neutralizing antibodies to the ancestral and the VOCs and found a large interindividual variation. We found that prior infection, combined with mRNA vaccination, dramatically enhanced neutralizing antibody titers against VOCs. In addition, we demonstrated that mRNA booster significantly enhanced neutralizing antibody titers to VOCs after vaccination with CoronaVac, an inactivated virus vaccine. We continue to examine the immunogenicity of various vaccines and booster combinations in combating the ever-changing SARS-CoV-2.