#055 COVID-19 Q&A #2 - Antibody-Dependent Enhancement, Cross-Immunity, Immunity Duration & More

Vaccine Science: Immunity

On the opposite end of the spectrum, individuals infected with HIV often have antibodies that do nothing to fight HIV. Some viruses, like HIV, use multiple strategies to evade antibodies.

"Some viruses, like HIV, use multiple strategies to evade antibodies. So what about other coronaviruses? Antibody titers in individuals that survived SARS-CoV-1 or MERS-CoV infections often waned after two to three years or were weak initially."

Gut Microbiome: Diet

Matthew Walker, who is the director of the Sleep Institute at UC Berkeley. Partial sleep deprivation can affect immunity.

"Matthew Walker, who is the director of the Sleep Institute at UC Berkeley. Partial sleep deprivation can affect immunity."

Vaccine Science: Immunity

This also suggests that the antibodies from these common cold coronaviruses may complicate accuracy of SARS-CoV-2 serological diagnostics, as people reinfected with common cold coronaviruses could score as false positive with some SARS-CoV-2 serological assays.

"For example, the J-curve study we mentioned earlier found that elite cyclists had four times as many sick days as the recreational cyclists and twice as many as the sedentary group. Other studies have found an increased rate of respiratory illnesses after intense endurance exercises that last at least 90 minutes in length. Shorter duration running events such as 5, 10 kilometers and half marathons did not appear to elicit an increased incidence of self-reported upper respiratory tract infections. Elite endurance athletes are exposed to many factors that could contribute to increased viral susceptibility. For example, they often attend events with large attendance, frequent traveling, psychological stress, potential nutritional deficiencies, lack of sleep, and more. However, when compared to other athletes that attend the same events and have similar risk factors, the endurance athletes still have a significant increased risk of illness compared to, for example, power or speed athletes. There are a couple of proposed mechanisms that might explain why extreme exercise may depress immune function. But before talking about the proposed mechanisms, I think that it goes without saying that extreme exercise, like that at the elite level, is very energetically demanding. Immune cell activation, such as the case when fighting off a pathogen, is also very energetically demanding. It seems very logical that there may be a triaging of the available energy to perform the exercise, since that is being forced, thus leaving the immune system temporarily unable to function optimally without the necessary precursors and energy it requires. All right, with that said, let's discuss the proposed mechanism one. The open window theory is characterized by short-term suppression of the immune system following an exercise. During exercise, stress hormones like cortisol increase in order to maintain adequate blood glucose. These stress hormones could transiently suppress immune function. Shorter exercises may not allow enough time for the pathogen to replicate, but a two-hour plus exercise may allow enough time for it to replicate to a critical threshold that the innate immune system cannot resolve. Some argue that the decrease in immune cells after exercise supports this theory, but as we will later discuss, the decrease in immune cells may actually be due to a beneficial relocalization of immune cells from the blood to tissues. So let's talk about mechanism number two. The immune system cannot handle the pathogen burden associated with a two-plus hour. While there may be a boost to the immune system in an intense 2-hour-plus exercise, as there is in a moderate 45-minute exercise, the burden on the immune system hits a tipping point that leaves it depleted. In support of this theory is the observation that vitamin C demand is increased in long-endurance exercises. For example, six trials involving more than 600 marathon runners, skiers, and soldiers reported 50% fewer colds when supplementing with vitamin C."

Vitamin D: Blood Level

For example, six trials involving more than 600 marathon runners, skiers, and soldiers reported 50% fewer colds when supplementing with vitamin C.

"Micronutrients, particularly vitamins C and D, support adaptive immunity via lymphocyte differentiation, proliferation, and homing, cytokine production, antibody production, and the generation of memory cells."

Vaccine Science: Immunity

Micronutrients are also involved in producing antimicrobial proteins, in differentiation and motility, in phagocytetic and killing activities of neutrophils and macrophages, and promotion of and recovery from inflammation.

"Vitamin A deficiency can impair the response to vaccination. A study in vitamin A deficient Indonesian children provided with vitamin A showed a higher antibody response to tetanus vaccination than seen in vitamin A deficient children."

Epigenetic Aging: Biological Age

Women have better immune responses to vaccinations than men, possibly due to the fact that estrogen is an enhancer of the humoral immunity, whereas testosterone is a suppressor.

"In other words, people with the same chronological age may have a vastly different biological age because of combined genetic and lifestyle factors. Some people may have a younger chronological age, but an older biological age, and vice versa. Data looking at responses to vaccines seem to suggest that biological age was a predictor of a better immune response. All in all, there are likely many factors that play a role in the variability in immune responses between different otherwise healthy individuals. Let's move on to the next question. Several articles mention possible higher risk among people who take ACE inhibitors or ARBs for hypertension. Is there actually a higher risk? Has this been tested? Let's start with a brief overview of the ACE receptor with respect to SARS-CoV-2. The SARS-CoV-2 virus attaches to the ACE2 receptor in order to infect a cell. Cells that lack ACE2 do not get infected with the virus. ACE2, also known as angiotensin-converting enzyme 2, is an enzyme found throughout the body to counteract the action of ACE1 in the renin-angiotensin system. Together, ACE1 and ACE2 function to regulate blood pressure and salt balance. ACE1, ACE2 imbalances such as higher ACE1 or lower ACE2 are seen in in many disease processes, such as atherosclerosis, high blood pressure, heart failure, chronic kidney disease, inflammation, and lung injury. When SARS-CoV-2 virus enters human cells via the ACE2 receptor, the ACE2 receptor is internalized into the cell with the virus. This results in a decrease of the number of functioning ACE2 receptors and worse disease severity. This has been shown to occur with the original SARS-CoV-1 virus. The decrease in ACE2 coupled with the cytokine storm creates a vicious inflammatory milieu, which can spiral out of control and lead to acute respiratory distress syndrome. This is supported by data from animal studies where acute lung injury decreases ACE2 receptor levels, and this exacerbates disease severity. But vitamin D increases ACE2 levels, and this was shown to protect against acute lung injury. In short, ACE2 is a key protective factor for severity of lung edema and acute lung failure. The epidemiology of COVID-19 also supports this. Those with decreased ACE2 levels are also those who have been seen to have more severe COVID-19 cases. This includes people with chronic diseases, elderly, and males. It has been hypothesized that since ACE inhibitors and ARBs, which are angiotensin 2 receptor blockers, increase ACE2, they may reduce the risk of severe disease in these populations that are at risk. Several cardiovascular societies have recommended continuing taking ACEs and ARBs. They argue that the increased protection from severe disease the ACEs and ARBs could provide is worth the theoretical tradeoff of increased risk of infection. In fact, there's a paper suggesting that ARBs should be used to treat COVID-19. A case population study from Madrid involving 1,139 cases and 11,390 control subjects assessed whether antihypertensive drugs affect the risk of contracting COVID-19 requiring hospitalization. Compared to the other hypertensive drugs, RAS inhibitors such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which increase ACE2 receptor levels, were not associated with an increased risk of COVID-19 requiring admission to the hospital. In fact, patients with diabetes taking these inhibitors had a decreased risk of COVID-19 requiring admission to the hospital, suggesting a possible decrease in disease severity. But more data is needed and only time will tell. Let's move on to the next question. Does COVID-19 cause irreversible damage to the lungs? Complications from severe COVID-19 such as pneumonia and acute respiratory distress syndrome can lead to irreversible damage. In patients with acute respiratory distress syndrome, fluid leaks into tiny air sacs in the lungs and prevents air exchange. Acute respiratory distress syndrome can lead to pulmonary fibrosis, which is a buildup of scar tissue in the lungs, decreased quality of life, and potentially death. Patients that develop acute respiratory distress syndrome from SARS-CoV-2 are much more likely to die. In 191 confirmed coronavirus patients in Wuhan, researchers found 50 of 54 patients who died had developed acute respiratory distress syndrome, while only 9 of the 137 survivors had acute respiratory distress syndrome. Survivors of acute respiratory distress syndrome are not out of the woods yet, though, because they have long-term lung damage, which may lead to a decrease in quality of life."

Vaccine Science: Immunity

Women have better immune responses to vaccinations than men, possibly due to the fact that estrogen is an enhancer of the humoral immunity, whereas testosterone is a suppressor.

"In other words, people with the same chronological age may have a vastly different biological age because of combined genetic and lifestyle factors. Some people may have a younger chronological age, but an older biological age, and vice versa. Data looking at responses to vaccines seem to suggest that biological age was a predictor of a better immune response. All in all, there are likely many factors that play a role in the variability in immune responses between different otherwise healthy individuals. Let's move on to the next question. Several articles mention possible higher risk among people who take ACE inhibitors or ARBs for hypertension. Is there actually a higher risk? Has this been tested? Let's start with a brief overview of the ACE receptor with respect to SARS-CoV-2. The SARS-CoV-2 virus attaches to the ACE2 receptor in order to infect a cell. Cells that lack ACE2 do not get infected with the virus. ACE2, also known as angiotensin-converting enzyme 2, is an enzyme found throughout the body to counteract the action of ACE1 in the renin-angiotensin system. Together, ACE1 and ACE2 function to regulate blood pressure and salt balance. ACE1, ACE2 imbalances such as higher ACE1 or lower ACE2 are seen in in many disease processes, such as atherosclerosis, high blood pressure, heart failure, chronic kidney disease, inflammation, and lung injury. When SARS-CoV-2 virus enters human cells via the ACE2 receptor, the ACE2 receptor is internalized into the cell with the virus. This results in a decrease of the number of functioning ACE2 receptors and worse disease severity. This has been shown to occur with the original SARS-CoV-1 virus. The decrease in ACE2 coupled with the cytokine storm creates a vicious inflammatory milieu, which can spiral out of control and lead to acute respiratory distress syndrome. This is supported by data from animal studies where acute lung injury decreases ACE2 receptor levels, and this exacerbates disease severity. But vitamin D increases ACE2 levels, and this was shown to protect against acute lung injury. In short, ACE2 is a key protective factor for severity of lung edema and acute lung failure. The epidemiology of COVID-19 also supports this. Those with decreased ACE2 levels are also those who have been seen to have more severe COVID-19 cases. This includes people with chronic diseases, elderly, and males. It has been hypothesized that since ACE inhibitors and ARBs, which are angiotensin 2 receptor blockers, increase ACE2, they may reduce the risk of severe disease in these populations that are at risk. Several cardiovascular societies have recommended continuing taking ACEs and ARBs. They argue that the increased protection from severe disease the ACEs and ARBs could provide is worth the theoretical tradeoff of increased risk of infection. In fact, there's a paper suggesting that ARBs should be used to treat COVID-19. A case population study from Madrid involving 1,139 cases and 11,390 control subjects assessed whether antihypertensive drugs affect the risk of contracting COVID-19 requiring hospitalization. Compared to the other hypertensive drugs, RAS inhibitors such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which increase ACE2 receptor levels, were not associated with an increased risk of COVID-19 requiring admission to the hospital. In fact, patients with diabetes taking these inhibitors had a decreased risk of COVID-19 requiring admission to the hospital, suggesting a possible decrease in disease severity. But more data is needed and only time will tell. Let's move on to the next question. Does COVID-19 cause irreversible damage to the lungs? Complications from severe COVID-19 such as pneumonia and acute respiratory distress syndrome can lead to irreversible damage. In patients with acute respiratory distress syndrome, fluid leaks into tiny air sacs in the lungs and prevents air exchange. Acute respiratory distress syndrome can lead to pulmonary fibrosis, which is a buildup of scar tissue in the lungs, decreased quality of life, and potentially death. Patients that develop acute respiratory distress syndrome from SARS-CoV-2 are much more likely to die. In 191 confirmed coronavirus patients in Wuhan, researchers found 50 of 54 patients who died had developed acute respiratory distress syndrome, while only 9 of the 137 survivors had acute respiratory distress syndrome. Survivors of acute respiratory distress syndrome are not out of the woods yet, though, because they have long-term lung damage, which may lead to a decrease in quality of life."