Hints of such mechanisms abound , Alter and Knipe said . For example , evidence points to partial immunity following the first dose of mRNA vaccines before the second booster shot . During this short window there are no neutralizing antibodies in the blood , yet the existence of partial protection suggests that the immune system is finding other ways to create protection .
“ What this tells us is that there are other players , not only antibodies — the innate immune system , the adaptive immune system , cellular immune response — and collectively , acting together , these various defenses can respond to the virus ,” Alter says .
Too much of a good thing
COVID-19 infection unfolds in two phases : An acute phase — lasting 5 to 7 days on average — is marked by the virus hijacking cells inside the body and by rapid replication .
This phase is followed by an inflammatory phase ( day 7-14 days in ), which is marked by the activation of multiple immune-signaling pathways that produce inflammatory molecules against the virus as well as against virus-infected human cells .
If misguided or too strong , this otherwise protective response can inflict serious collateral damage to cells , tissues and organs . At its most extreme , inflammation gone awry can unleash a so-called cytokine storm that overwhelms the body , damages organs and , at times , leads to death .
One area of active interest is mapping the precise steps and cascade of inflammatory mediators that directly or indirectly promote disease . Such knowledge could inform the design of precision-targeted anti-inflammatory treatments that target specific pathways .
Currently , the exuberant inflammation of COVID-19 is managed with an old-school immune-modulating drug , dexamethasone , a corticosteroid that suppresses overall immunity .
Research has shown that the drug can prevent death among those with severe lung disease caused by COVID-19 . Yet , the therapy carries the traditional risks of corticosteroids , such as elevations in blood pressure , cholesterol and blood sugar , and must be used with caution in patients who have weakened immune systems because it could severely suppress their ability to fight infection .
Identifying the cascade of biochemical events that culminate in a cytokine storm is critical to designing more finely tuned therapies that do not dampen overall immunity .
Defining the right window for timing of treatment is an evolving question .
“ Timing is very important in that if you give it too soon , you ’ re going to block the antiviral response ,” Knipe says . “ If you don ’ t give it soon enough , you won ’ t block the immunopathology or the inflammatory response .”
“ This is the whole issue that we ’ ve been grappling with in pathogenesis — the complexity of the host immune response and the acute respiratory distress and the virus ,” Knipe adds . “ How do we toggle and finetune the treatment so precisely that we eliminate the immunopathology but still allow the immune response to control the virus .”
In addition to inflicting damage on cells and organs , severe inflammation may interfere with the body ’ s ability to establish long-term immune memory , according to research led by MassCPR member Shiv Pillai . His work shows that people with COVID-19 who experience cytokine storms may also end up making fewer antibody-producing B cells , which are so critical to creating sustained immune memory .
The root of dysfunction , the study shows , is one particular cytokine , TNF , which appears to interfere with the formation of germinal centers — areas in the lymph nodes and spleen where antibody-producing B cells grow and proliferate . The findings offer one possible explanation for the non-durable immunity seen in COVID-19 .
How long does immune memory last ?
Two of the most critical questions since the start of the pandemic have been : How long does the human immune system retain memory of SARS-CoV-2 ? Does the immune memory vary from person to person and , if so , what drives this variation in immune longevity ?
Research led by MassCPR scientist Duane Wesemann offers some answers . The work shows that while antibodies against SARS-CoV-2 declined in most individuals after disease resolution , a subset of patients sustained antibody production for several months following infection .
These antibody “ sustainers ” also had shorter disease course , suggesting that those who overcame the disease faster also mounted more lasting immunity to the virus . The samples used in the study , however , were obtained from people with mild to moderate disease and excluded individuals at the two extremes of the illness spectrum — asymptomatic infections and those withs severe disease .
Another study , led by MassCPR member Richelle Charles , an infectious disease expert at Mass General , explored the question of immune memory in a group that consisted mostly of individuals with severe infections .
The work showed that one type of antibody , IgG , persisted for at least three months following infection , offering a window into the longevity of immune protection after infection . By contrast , two other types of antibodies IgA and IgM decayed within two and half months or less after infection .
Re-infection vs . persistent shedding
Scientists have learned that a small number of people may become re-infected with the virus . Why such reinfections occur remains to be elucidated . Yet another subset of individuals appear to never clear the virus but instead subdue its replication to chronically low levels .
Telling the two groups apart has been challenging . The question often arises when clinicians encounter patients with documented prior COVID-19 and subsequently test positive by PCR , a test that viral RNA .
The Centers for Disease Control and Prevention ( CDC ) defines reinfection as having a positive PCR test and symptoms suggestive of COVID-19 at least 45 days following an original diagnosis of COVID-19 . An individual who has a second positive PCR , even without symptoms , 90 days or longer after an initial positive PCR test is also considered re-infected .
“ We see this a lot , but we do not know whether it ’ s a new infection , chronic infection or lingering shedding from the prior infection ,” said Charles during a recent session of the pathogenesis working group . “ The question we ’ re interested in is how the immune response in persistent shedders or chronically infected individuals may be different from individuals who are able to clear the virus , and what factors make individuals susceptible to reinfection ,” Charles added . She is conducting ongoing research in an effort provide some answers .
Charles and colleagues are working to analyze the antibody