So far in this series, I’ve described the intricate dance between SARS-CoV-2 and innate immunity. The net result is the virus can arrest and delay the innate immune response long enough to enter and exit, initiating a new round of infections, both in those who have been infected for the first time and those who have had prior immunity either as a consequence of natural infection or vaccination.
Fortunately, the news is not all bad. The more we understand what SARS-CoV-2 must do to evade our natural immune defenses, the more opportunities we have to create new ways to prevent and treat disease. What follows is a summary of what we’ve learned so far.
What accounts for asymptomatic transmission?
Innate immunity is the body’s first line of defense against invading pathogens. If a virus can succeed at disarming the innate immune response, it gains a critical advantage. The advantage is time—time to reproduce in abundance and infect others before alarm bells begin to sound.
SARS-CoV-2 can spread from one person to another asymptomatically—that is, without any obvious symptoms. Studies show that asymptomatic transmission is the primary mode of transmission of Covid-19, making up more than half of all infections. Children, though they rarely suffer serious disease, often spread the virus amongst each other and to adults.
We now know why this happens. The first symptoms of infection are not a consequence of SARS-CoV-2 replicating in the body. Rather, most Covid-19 symptoms, such as fever, muscle aches, and fatigue, are caused by an immune reaction to infection, not from damage caused by the infection itself. It is common for similar symptoms to appear in reaction to vaccinations against Covid-19 and other infectious diseases. Again, these aren’t a result of the virus replicating, but the body’s reaction to immunization.
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Figure 1 shows that concentration of SARS-CoV-2 peaks well before people feel ill. It is during this phase, when the virus is actively suppressing the innate immune response and more specifically, inhibiting of interferons and interferon-stimulated genes, that most infection takes place. Once innate immunity kicks in, viral concentrations fall precipitously, as does transmission. (For more detail on this topic, revisit the first twelve parts of this series.)
Why do some people fall severely ill and die?
Most infections with SARs-CoV-2 do not end up with serious disease. Depending on the variant, up to half people never know they’ve been infected, while another 25 percent may experience only mild cold-like symptoms. But some Covid-19 cases can be very serious and even life-threatening.
After evaluating the literature, I have come to the conclusion that the major determinant of critical illness is how rapidly and efficiently the body engages the immune system by activation of interferon to suppress virus replication days three through eight. If interferon is induced and the innate immune system finally kicks in despite the virus’ best efforts to thwart it, people will go on to have either no symptoms or very mild symptoms. However if there is any glitch in the late activation of innate immunity, trouble is likely to ensue.
Recent data suggests one of the reasons children have a lower instance of disease is because their innate immune system is more active, in large part due to early and robust interferon synthesis that induces broad viral protection. One of the reasons people of advanced age may suffer more serious consequences of infection is the declining activity of the innate immune system as well as higher incidence of anti-interferon antibodies, which I will discuss shortly.
The primary agent in the activation of the innate immune system is interferon. People who are defective in generating an interferon response have a far greater chance of being hospitalized and falling ill than those who aren’t. Those who have mutations either in the interferon genes themselves or the pathways that induce interferon are more likely to fall ill. Either you have defective interferon, you have defects in inducing interferon, or you have defects in interferon-stimulated genes.
An additional cause are those people who have antibodies to interferon itself. The difference in severity isn’t a matter of whether SARS-CoV-2 suppresses the immune system, but how well the body recovers and restores the interferon response.
Another indication that interferon plays a critical role in disease severity is that pre- or late treatment with interferon in cell culture prevents virus replication. Regretfully this isn’t as easy to accomplish in humans, as interferon itself induces flu like symptoms, though it has been approved as a drug for diseases like cancer.
There is an alternative pathway to induce the genes that interferon would normally activate, the proinflammatory STING (Stimulator of Interferon Genes) response. STING activates many of the same downstream effector proteins that interferon does. Critically, the STING pathway appears to bypass the many blockades SARS-CoV-2 mounts against the innate immune response.
We know that STING is activated by small cyclic dinucleotides. Researchers have taken advantage of this understanding to devise drugs such as cyclic nucleotide antagonists. One such is diABZI.
Why can the virus reinfect people who have already been infected or vaccinated?
We now know that protection against infection and hospitalization wanes dramatically, particularly with respect to some of the variants, Beta, Gamma, and Delta. We’re still waiting for the second shoe to drop vis-a-vis serious disease and death.
As immunity continues to wane, it seems likely that not only will protection against infection and hospitalization wane, but also serious disease and death. We now know that protection against serious disease and death wanes for natural infections either because the virus escapes immune detection or because levels of protective neutralizing antibodies fail to protect against progressive infection.
The evidence that the virus can cause substantial incidence of severe illness and death has emerged from new waves of infections in populations previously infected. For example in Manaus, it is estimated that in the first wave over 70 percent of people were infected. Even so, the subsequent wave by the Gamma variant caused as much, if not more, severe disease and death than the previous wave. The experience of India was similar. Despite a massive first wave, the second wave wrought absolute havoc, with an official death toll of 400,000 that is estimated to be anywhere between two and four million. I for one do not expect our vaccines to perform much better protecting against infection than natural protection. This view may be overly pessimistic, but without further evidence it seems to be the safest assumption.
Data from Israel shows us that a third dose of the mRNA vaccine can significantly improve a person’s level of immunity and protect against severe disease. Efficacy increased from about 39 to 41 percent to 88 to 91 percent when a booster was administered five to six months after the second dose.
Up to now I’ve explained how the virus facilitates its entry and exit by repressing innate immunity long enough to enter the cell, replicate to high numbers, and infect others. Interestingly it is the same phenomenon that allows the virus to reinfect people who have been already infected or vaccinated once their initial first antiviral antibodies fades, which occurs inevitably.
After the initial antibodies are no longer fully effective, protection depends on immunological memory that is carried out by long term memory B cells and T cells. Not surprisingly, the same tricks the virus uses the first time to ward off the innate immune system work the second time as well. Once a high level of immunity is no longer there, the virus can enter, suppress immunity, shield itself from recognition by memory B cells and T cells, replicate, and exit before memory kicks in.
It is this observation that allows us to understand why coronaviruses have repeated cycles of infection. In the United States, we are in the midst of our fourth wave, as are many other countries. The only thing so far that distinguishes the cycles of infection of Covid-19 from the cold viruses and influenza is there are two waves, one in the summer and one in the winter, likely driven by our gregarious behavior.
The current hope that many hold out for protection against severe disease and death mediated by an immune memory response distinguishes the patterns of infection of Covid-19 from cold and influenza virus epidemics is that for Covid-19 triggers two waves of infection, possibly because of increased transmissibility relative to the other two infections.
What does this tell us about our future?
Suppression of innate immunity is vital to asymptomatic spread of SARS-CoV-2 and its ability to get in and out quickly before the immune system can be triggered and get in again before memory can be effective. Anything we can do to limit the virus’ ability to either strengthen innate immunity or knock out specific pathways the virus uses to counter innate immunity will give us a definite advantage.
We now know the proteins the virus has. Each one of these proteins plays a critical role in immunity and gives us a wealth of targets. Each one is a new target. With HIV, we had about eight targets. With SARS-CoV-2, we could have as many as, if not more than, 25 targets. Table 1 shows these targets of opportunity. It is time to have a warp speed effort to develop many classes of antiviral drugs. We are just scratching the surface.
Source : https://www.forbes.com/sites/williamhaseltine/2021/09/20/pandemic-cycles-of-covid-19-sars-cov-2-immune-suppression-helps-us-understand-repeated-cycles-of-viral-infection-and-vaccine-breakthrough/2391