COVID-19 Research Update
March 30, 2021
During the COVID-19 pandemic, it is vital to make objective and informed decisions that affect your family and loved ones. As part of Princeton Longevity Center’s strategic partnership with PinnacleCare, we are excited to bring you their Pandemic Response Research updates as a complimentary resource through the remainder of this crisis. These updates will bring you factual, objective, scientific information to help make safe decisions for you, your family and your community. Updates, while scientifically based, are easy to understand and will include both resources and references for a more clinical insight.
Worldwide Prevalence of COVID-19
In order to estimate the number of people in the world who have been infected with SARS-CoV- 2, researchers searched the published literature for all available studies investigating the presence of antibodies (Chen et al., 2021). Based on the examination of articles published in the year between December 1, 2019 and December 22, 2020, 404 relevant articles were available.
There was a large amount of variation between different studies and in different geographical areas. The area with the lowest proportion of the population with antibodies towards SARS- CoV-2 was found in the Western Pacific at 1.7%.
The authors conclude that antibody-mediated herd immunity from natural infection is far from being reached in most settings, and the information in their study also allows for the estimation of the actual number of infections in an area in relation to the number of confirmed cases.
Update to Recommendations for Nursing Homes
The Centers for Medicare and Medicaid Services in collaboration with the CDC issued updated guidance for visitation of nursing homes as vaccination programs for COVID-19 continue to expand(CMS,2021).
The updated recommendations also emphasized that compassionate care visits should be allowed at all times, regardless of a resident’s vaccination status, the county’s COVID-19 positivity rate, or an outbreak at the facility. Compassionate care visits include visits for a resident whose health has sharply declined or is experiencing a significant change in circumstances. Along with the updated recommendations, it is also recommended that facilities, residents, and families adhere to COVID-19 infection control measures, including maintaining physical distancing and conducting visits outdoors whenever possible. This continues to be the safest way to prevent the spread of COVID-19, particularly if either party has not been fully vaccinated.
COVID-19 Vaccine Updates
A press release from Novavax reported the final analysis of the results from the Phase 3 trial performed in the United Kingdom for their COVID-19 vaccine candidate in addition to the complete analysis of the results from a Phase 2b trial performed in South Africa (Novavax, 2021). This two-dose vaccine is a protein-based vaccine that includes the spike protein from SARS-CoV-2.
Based on the Phase 3 trial, the vaccine reduced the risk of mild, moderate, and severe disease caused by the original strain of SARS-CoV-2 by 96.4%.
The trial performed in the United Kingdom also allowed for a determination of the efficacy against the B.1.1.7 variant, which was found to be 89.7% and similar to the efficacy observed for the original strain. The efficacy 14 days after the first dose was found to be 83.4%, and there was not a difference in the efficacy for individuals over the age of 65.
In the clinical trial performed in South Africa, the B.1.351 variant was the prevalent strain of virus circulating, and the efficacy of the vaccine was reduced to 55.4%. Vaccine-induced protection began around 14 days after the first dose with an increased efficiency seven days after the second dose.
In both the United Kingdom and South Africa based trials, the vaccine had a 100% efficacy against severe disease, hospitalization, and death.
Prevention of Asymptomatic Infections
Information from the use of the Pfizer-BioNTech vaccine in real-life situations in Israel suggests that the vaccine is able to prevent asymptomatic disease as well as symptomatic disease.
This determination is important because it was not evaluated in previous clinical trials, and it is not known if vaccinated individuals can transmit the virus to others unknowingly due to asymptomatic infections. Based on the data collected during the vaccination campaign in the country, the vaccine was found to be at least 97% effective against symptomatic COVID-19 cases, hospitalizations, severe and critical hospitalizations, and deaths (Pfizer, 2021).
Additionally, researchers found a vaccine effectiveness of 94% against asymptomatic SARS- CoV-2 infection. This data was collected when it was estimated that more than 80% of the cases in Israel were caused by the B.1.1.7 variant.
A study in the United States performed for individuals who were screened before having a procedure performed at Mayo Clinic locations throughout the United States between December 17, 2020 and February 8, 2021 also allowed for evaluation of the efficacy of both mRNA-based vaccines against asymptomatic infection (Tande et al., 2021). Researchers investigated the risk of a positive test for COVID-19 in asymptomatic individuals who had received at least one dose of an mRNA-based vaccine compared to those who had not yet been vaccinated. Within the group that had received at least one dose of vaccine, 23% were fully vaccinated.
Overall, 1.4% of the vaccinated participants in the study tested positive for COVID-19, and 3.2% of unvaccinated individuals tested positive. Compared to individuals who had not been vaccinated, individuals who had received their first shot more than 10 days before had a 79% reduction in the risk of a positive COVID-19 test. There was an 80% reduction in the risk of a positive molecular screening test among individuals who had received two doses of vaccine compared to those who were not vaccinated.
The results show that both the first dose and second dose lower the risk of asymptomatic infection from SARS-CoV-2 compared to individuals who have not been vaccinated.
Effectiveness of the Pfizer-BioNTech at Skilled Nursing Facilities
Vaccination in older individuals is often less effective due to reductions in the activity of the immune system with age. In order to get more information on the effect of the Pfizer-BioNTech vaccine in individuals who are more medically frail, older, and have multiple underlying medical conditions researchers investigated a COVID-19 outbreak at two skilled nursing facilities occurring after the start of vaccination at the facilities (Britton et al. 2021).
The study included 463 residents in two facilities with 24.8% of the residents having had a COVID-19 diagnosis prior to the start of the study. Both facilities provided weekly testing for staff and residents, and site-wide testing was implemented if a positive test was reported. The study began on December 21, 2020 at one facility and December 29, 2020 at the other, which corresponded to the start of the vaccination campaigns, and the trials ended on February 9 and February 12, 2021, respectively. By the end of the study, 65.7% had received two doses of vaccine, 15.6% had received a single dose, and 18.8% had not received any doses. In the report, partial vaccination was defined as the period more than 14 days after the first dose through seven days after the second dose. There were 97 cases of COVID-19 in residents of the facilities during the study with 41% of the cases occurring at one facility and the remaining at the second facility. It was determined that 88.7% of cases were symptomatic.
Partial vaccination had an estimated effectiveness of 63% against SARS-CoV-2 infection among residents who were over 65 years of age with a high prevalence of underlying medical conditions.
Due to the timing of the outbreak and the number of participants who had been fully vaccinated or not vaccinated, it was not possible to determine the efficacy for the fully vaccinated participants from the available data. The level of efficacy for the partially vaccinated individuals is similar to the previously reported estimates from the broader population, however.
Side Effects from Vaccination
With the increasing number of people receiving vaccinations, more information is available about side effects from the shots (Moyer, 2021 and Van Beusekom, 2021). Researchers have identified that, as with other vaccinations, women are more likely to experience side effects after receiving a vaccine. Most often, the side effects are mild and short lived, and the symptoms are due to reactions from the immune system mounting a response to the vaccine.
Additional investigation into the serious anaphylaxis reactions observed after inoculation with the mRNA-based vaccines has shown that the reactions continue to be rare (Blumenthal, et al., 2021). A study of 64,900 employees at two Boston hospitals included those who were vaccinated between December 16, 2020 and February 12, 2021, and 40% of the group received the Pfizer-BioNTech vaccine with the remaining receiving the Moderna vaccine. In the study, researchers found that 2.1% of those vaccinated had an acute allergic reaction, but only 0.025% had an anaphylactic reaction. The description of acute allergic reactions included itching, rash, hives, swelling, and/or respiratory symptoms. Acute allergic reactions were reported more often with the Moderna vaccine with 2.20% compared to 1.95% of individuals reporting reactions. The difference between the values was statistically significant, but the magnitude of the difference was small.
Anaphylaxis reactions were reported in 16 individuals, with 7 cases with the Pfizer-BioNTech vaccine and 9 with the Moderna vaccine. The difference between the incidences of anaphylaxis for the two different types of vaccine was not statistically significant, which means that both have the same chance of triggering a reaction. The majority of the people who had an anaphylactic reaction were women (94%), and 31% with a reaction had a history of a previous incidence of anaphylaxis. There were approximately 4,000 individuals out of the 64,900 participants who had severe food or medication allergies who were safely vaccinated.
The authors stressed that 98% of the individuals vaccinated in this study did not have any symptoms of an allergic reaction after receiving an mRNA COVID-19 vaccine.
In the 0.025% of the group who did have an anaphylactic reaction, all individuals recovered and none experienced symptoms of shock or required endotracheal intubation for assistance in breathing.
AstraZeneca released the interim results from the Phase 3 trial of its vaccine developed with Oxford University that was conducted in the United States (AstraZeneca, 2021). The vaccine was given in two doses four weeks apart in this trial. However, other clinical trials that finished after the trial in United States started have indicated that an extended time of up to 12 weeks led to a greater efficacy, which will likely be implemented in the future.
Based on the analysis of vaccination of 32,449 participants in the United States trial, the vaccine was found to be 79% effective in the prevention of symptomatic COVID-19 and 100% effective at preventing severe or critical disease and hospitalization.
Of those included in the interim analysis, 79% were white/Caucasian, 8% Black/African American, 4% Native American and 4% Asian, and 22% of participants were Hispanic. Additionally, approximately 20% of participants were 65 years and over and approximately 60% had co-morbidities associated with an increased risk for progression of severe COVID-19, such as diabetes, severe obesity or cardiac disease. When participants older than 65 years of age were analyzed separately, the efficacy was still 80%, suggesting that the vaccine has a similar effectiveness in older individuals.
No safety concerns were noted during the clinical trial. With the question of clotting abnormalities that has arisen in Europe, the independent data safety monitoring board of the trial conducted a specific review of thrombotic events, as well as cerebral venous sinus thrombosis (CVST), with the assistance of an independent neurologist.
No increased risk of thrombosis or events characterized by thrombosis was found among the 21,583 participants receiving at least one dose of the vaccine, and the specific search for CVST found no events in this trial.
At this time, the AstraZeneca-Oxford vaccine has not been authorized for use in the United States, but company officials stated they would use the results from this most recent trial to prepare for filing for an Emergency Use Authorization in the near future.
As mentioned above, there have been preliminary reports in Europe of a possible association of the use of the AstraZeneca-Oxford vaccine with abnormal clotting symptoms (Vogel, 2021). The constellation of symptoms includes serious clotting events that are so severe that the blood cells, called platelets, involved in clotting are depleted from other areas in the body thereby also resulting in uncontrolled bleeding events. There were also early reports of specific batches of vaccine being associated with the syndrome. However, the individuals currently identified received vaccine from different batches, and a manufacturing problem is therefore unlikely.
The number of events identified so far have been very low compared to the millions of doses of the vaccine that have been delivered, and there are several naturally occurring conditions that have similar symptoms, making it difficult to determine the cause of the events.
In the United Kingdom, which has administered the vaccine to more than 10 million people, no cases of the clotting disorder have been reported. In Austria, one case was identified with four cases in Norway and seven cases in Germany. Based on the reported incidences, a group of vaccine experts in Europe “agreed unanimously that there seemed to be a pattern here and that a link to the vaccine was not implausible and that this should be investigated.”
However, the European Medicines Agency, which is similar to the FDA and approves new medicines in the European Union, has stated that vaccinations should continue as “the vaccine’s benefits outweigh any risks.”
The WHO released a statement on March 19, 2021 stating that:
The available data do not suggest any overall increase in clotting conditions such as deep venous thrombosis or pulmonary embolism following administration of COVID-19 vaccines. Reported rates of thromboembolic events after COVID-19 vaccines are in line with the expected number of diagnoses of these conditions. Both conditions occur naturally and are not uncommon. They also occur as a result of COVID-19. The observed rates have been fewer than expected for such events.
They also mentioned that there have been only 18 reported cases of CVST out of a total of more than 20 million vaccinations with the AstraZeneca-Oxford vaccine in Europe and more than 27 million vaccinations of the same vaccine (called Covishield) manufactured by the Indian company Serum Institute of India (WHO, 2021).
Based on the announcements from the WHO, EMA, and regulators in the United Kingdom most countries have resumed use of the AstraZeneca-Oxford vaccine in their vaccination campaigns.
COVID-19 Treatment Updates
Aspirin reduces the risk of clot formation and is often used in low doses for prevention of thrombosis in individuals with hypertension and other cardiovascular risk symptoms. A clinical trial has indicated that it can reduce the risk of mechanical ventilation, intensive care unit admission, and in-hospital mortality in individuals with COVID-19 (Chow et al., 2021). The clinical trial included 412 participants who were admitted to the hospital for treatment for COVID-19 between March, 2020 and July, 2020. Within the study group, 76.3% did not receive aspirin, and 23.7% received aspirin within 24 hours of admission or during the 7 days before admission. Of those who received aspirin, 75.5% were taking it before admission, and 86.7% received it within 24 hours of hospital admission. Participants who received aspirin treatment had higher rates of hypertension, diabetes mellitus, coronary artery disease, and renal disease than those who did not receive the treatment, and they also were more likely to have been prescribed beta-blockers for hypertension and have liver disease.
At the time of admission, participants who were taking aspirin required less oxygen support than those not taking aspirin. The researchers also found that aspirin use was independently associated with a reduced risk for mechanical ventilation (54%), a reduction in risk for intensive care unit admission (53%), and in-hospital mortality (57%) without a statistically significant increase in major bleeding in patients who received aspirin. This improvement was seen even though the participants as a group were more likely to have conditions that increase the risk of severe COVID-19 symptoms.
This trial was not large enough to determine what the optimal timing for dosing of aspirin was, and whether individuals who had been taking aspirin before infection fared better than those who began taking aspirin at the time of hospital admission. However, as an inexpensive, readily available medication with few side effects, its use can be further investigated.
The National Institutes of Health announced that they are halting the trial of convalescent plasma for the treatment of COVID-19 in individuals treated in emergency departments with mild to moderate symptoms due to a lack of a statistically significant benefit in this group (NIH, 2021).
The decision was made after review of the interim analysis of the trial data that showed that the treatment caused no harm but was unlikely to benefit this group of individuals.
The trial was being conducted at 47 hospital emergency departments around the country and had enrolled 511 of the expected 900 participants. Participants were required to be treated at an emergency department within one week of the start of mild to moderate symptoms and also had at least one risk factor for severe COVID-19, including obesity, hypertension, diabetes, heart disease, or chronic lung disease.
Long Duration COVID-19
Three studies were published describing the characteristics of individuals who developed the extended form of COVID-19 called long-COVID.
The first study investigated individuals, mainly from the United Kingdom, who tracked their symptoms using a cell phone app called the COVID Symptom Study (Sudre et al., 2021). Users of the app were asked to report their health status daily through a series of questions and any COVID-19 tests with results. The information for the study was collected between March 21, 2020 and September 2, 2020 and included data from 4,223,955 adults. From the whole group, 4,182 individuals who tested positive for COVID-19 and had data entered over sufficiently long periods of time were included in the study. A control group was selected from the app users who did not report testing positive for COVID-19.
The onset of disease was defined in the study as the first day a person reported at least one symptom. The end of disease was defined as the last day a symptom was reported before a person reported feeling healthy for the next consecutive seven days. The definition for long- COVID in this study was set at symptoms that persisted for more than four weeks.
The overall median duration of symptoms was 11 days for the entire study group. There were 13.3% of the participants who had symptoms for more than 4 weeks, 4.5% of the total group had symptoms for more than 8 weeks, and 2.6% had symptoms for more than 12 weeks.
The most common symptoms that were reported in individuals with symptoms for more than 4 weeks were fatigue (97.7%) and intermittent headache (91.2%).
The symptoms reported by people with long-COVID differed from those associated with short- COVID. People with prolonged symptoms were more likely to add symptoms not on the checklist compared to those with short-duration COVID. For example, 6.1% of individuals with long-COVID reported the cardiac symptoms of palpitations and tachycardia while only 0.5% of those with short-COVID reported the symptoms. Additional examples of symptoms that were disproportionately more frequent in those with long-COVID included concentration or memory issues (4.1% versus 0.2%), tinnitus and earache (3.6% versus 0.2%), and peripheral neuropathy symptoms such as pins and needles or numbness (2% versus 0.5%). Most of these symptoms were reported for the first time three to four weeks after initial symptom onset. The symptoms observed in individuals with symptoms that lasted longer than 4 weeks were grouped into two categories by the researchers, those reporting exclusively fatigue, headache and upper respiratory complaints such as shortness of breath, sore throat, persistent cough and loss of smell and those with additional multisystem complaints, including ongoing fever and gastroenterological symptoms.
Based on the characteristics of the group, the researchers were able to construct an algorithm to predict which individuals had the highest risk of persistent symptoms in the form of long- COVID.
Individuals who reported more than five symptoms in the first week had a statistically significant increase in the risk of experiencing long-COVID.
This correlation was evident in both men and women as well as all age groups. There were certain symptoms that were also more likely to be reported in the first week by individuals who went on to have long-COVID.
In adults over 70 years, loss of smell was the most predictive symptom of long-COVID, and this symptom was generally less common overall during the initial infection in this age group. Using their model, they were able to predict 73.4% of cases of long-COVID in another sample group.
A second study of individuals with long-COVID occurred in the United States and collected data from medical records of patients in The University of California COVID Research Data Set (UC CORDS) who had had COVID-19 (Huang et al., 2021). Information from 1,407 participants with confirmed COVID-19 was included, and symptoms and duration of symptoms were accessed from medical records. In the study, the acute infection was defined as from day zero (or the day of diagnosis) until day ten after diagnosis, and long-COVID was defined as individuals with persistent symptoms 61 days or more after diagnosis.
In this study, 27% of the participants were found to still have symptoms of COVID- 19 sixty-one (61) days from diagnosis.
The individuals with persistent symptoms were of all age ranges, including children as young as 5. As in other studies, female participants were more likely to have long-term symptoms (59%), but there were no differences based on ethnicity or race that could be determined because of the lack of complete data in the group of participants.
As with the previously mentioned study, the researchers found that the types of symptoms seemed to cluster together during the initial infection and during the long-COVID period. They identified five different clusters that were more likely to occur together, which are listed in Table 1.
Table 1. List of symptoms in each cluster.
However, the researchers found that the symptoms reported by the participants were not necessarily constant over time. Recording the changes in symptoms can be difficult because some symptoms, such as cognitive impairment and brain fog, are not initially included in assessments after respiratory infections.
Importantly, the researchers found that of those participants who developed long- COVID, 32% were found to be asymptomatic during the initial infection.
Of those that had symptoms during the initial infection, the most prevalent (in descending order) were dyspnea, cough, fever, chest pain, diarrhea, anxiety, and fatigue.
The researchers in this study also developed an algorithm to predict which individuals had the highest risk of developing long-COVID. They found a correlation between individuals who were asymptomatic during the initial infection, a correlation with people who had heart palpitations during the initial infections, and a correlation with people who had chronic rhinitis.
Based on these two reports, it can be concluded that a substantial number of people who have had COVID-19 will have long-term consequences from the infection that could affect their quality of life and ability to function for quite some time after recovering from the initial infection. Additionally, even those who had no symptoms during the initial infection can have long lasting effects.
There are also preliminary reports that some individuals with long-COVID have had improvement in their symptoms after they are vaccinated for COVID-19 (Belluck, 2021 and Arnold et al., 2021). Anecdotal reports from doctors treating individuals with long-COVID suggest that in the days after the second shot of mRNA vaccines symptoms start to decrease. However, at this point, too few individuals with long-COVID have been vaccinated to allow for a statistical evaluation of the potential effect.
In the United Kingdom, a study reported as a preprint was investigating the safety of vaccination in individuals with long-COVID (Arnold et al., 2021). They found that “receipt of vaccination with either an mRNA or adenoviral vector vaccine was not associated with a worsening of long- COVID symptoms, quality of life, or mental wellbeing.” When compared to unvaccinated participants with long-COVID, there was a small overall improvement in long-COVID symptoms. The researchers found that symptoms worsened in 14.2% of unvaccinated individuals and in 5.6% of vaccinated individuals. There was also an increase in symptom resolution in those who were vaccinated (23.2% versus 15.4%). They did not observe a difference in the response between the different vaccines used.
There are some people with long-COVID who have reported that vaccination has made their symptoms worse, however (Belluck, 2021). Researchers interviewed by the New York Times indicate that these differences in response may help to differentiate what is happening in different people. One scientist, Dr. Akiko Iwasaki from Yale University, mentioned that the improvements observed after vaccination could also be temporary based on experience in other autoimmune-based diseases, which is one of the proposed causes of long-COVID.
Long-Term Effects after Severe COVID-19
The third study on the long-term effects after recovery from acute infection with SARS-CoV-2 was performed in France (Writing Committee for the COMEBAC Study Group et al., 2021). In this study, researchers investigated the outcome of participants four months after recovery from severe COVID-19 that required hospitalization. The 478 participants were hospitalized between March 1 and May 29, 2020 and were interviewed by telephone assessment four months after they were discharged. Individuals who reported still having symptoms were also evaluated at an outpatient clinic.
During the initial telephone interview, 51% of the participants reported at least one symptom that they did not have before their SARS-CoV-2 infection. The symptoms reported included fatigue in 31%, cognitive symptoms in 21%, and new-onset shortness of breath in 16%. CT scans located lung abnormalities in 63%. Most were ground glass opacities, but fibrotic lesions (scar tissue) were also observed. In participants who had developed acute respiratory distress syndrome (ARDS) while hospitalized, 39% had fibrotic lesions. There was a reduction in heart function (measured by a left ventricular ejection fraction less than 50%) in 10% of the individuals treated in the intensive care unit, corresponding to 8 of 83 participants, and new-onset chronic kidney disease in 2% of participants treated in the intensive care unit. The rate of anxiety in individuals treated in the intensive care unit was 23%, the rate of depression was 18%, and the rate of posttraumatic stress syndrome was 7%.
With the large number of people who have been hospitalized and survived COVID- 19 in the United States, the results of this study suggest that there will be a large number of people who were hospitalized for COVID-19 that may have long-term health effects from the disease.
SARS-CoV-2 Variant Updates
Results from the characterization of the related variants designated B.1427 and B.1429 that were first identified in California have been reported, and based on the evaluation, the variants have been classified as variants of concern by the CDC due to the increased rate of transmission (Soucheray, 2021).
It is estimated that B.1427 and B.1429 are 20% more transmissible than the original strains of SARS-CoV-2.
For comparison, the B.1.1.7 variant that originated in the United Kingdom has been found to be 50% more transmissible than the original form of SARS-CoV-2. However, B.1427 and B.1429 do not have the same mutations that lead to avoidance of the immune response observed with B.1.351 and P.1.
Officials suggest that the spread of the different variants, such as B.1.1.7, B1427, and B.1429, may be contributing to the emergence of new hot spots of SARS-CoV-2 transmission around the United States in the Upper Midwest, Northeast, and Mid-Atlantic. As of March 10, 2021 the share of cases attributed to B.1.1.7 in the United States was 36% (Achenbach et al., 2021).
Immune Response to Variants
There have been numerous reports that some of the variants of SARS-CoV-2 are able to escape immunity provided by antibodies, and that vaccines may be less effective against some of the variants. Two new studies showed that mutations in the spike protein of B.1.351 reduce the interaction between the antibodies and the virus, and a third showed that the AstraZeneca vaccine is ineffective against the B.1.351 variant (Garica-Beltran et al., 2021, Liu et al., 2021, and Madhi et al., 2021). The effect of the mutations in B.1.1.7 have had less of an effect on vaccine efficacy because of the placement of the mutations, but there is a reduction in the interactions with certain antibodies that are part of authorized antibody treatments for COVID-19 (Wang et al., 2021).
While changes in the spike protein are expected to alter the response of antibodies to SARS- CoV-2 infection, it has not yet been determined how the mutations will affect the response of T cells produced from natural infection or vaccination. Because the role of T cells in the immune response is less about preventing an infection by neutralizing the virus, T cells may still be effective through interaction with parts of the virus other than the spike protein. Researchers have therefore investigated the killer T-cell and helper T-cell responses to exposure to the variant forms of SARS-CoV-2 (Tarke et al., 2021).
In the study, T cells from individuals who had recovered from the initial strain of SARS-CoV-2 and from those vaccinated with either the Pfizer-BioNTech or Moderna vaccine were tested against B.1.1.7, B.1.351, P.1, and CAL.20C (one of the strains spreading in California). Based on their results, they found that most of the areas that the T cells interact with were not mutated in the variant versions of the virus, and 93% of helper T cells and 97% of killer T cells interact with regions of the virus that are not changed in any of the variants. Therefore, the response of the T cells was also not substantially affected by mutations found in the SARS-CoV-2 variants.
The authors conclude that this lack of an effect on the T-cell response would not be expected to prevent a subsequent SARS-CoV-2 infection, but it is plausible that during an infection the T cells would be able to respond to the virus and reduce the severity of the disease.
Similar evidence has been observed in reports of individuals with SARS-CoV-2 with an early T cell response that were associated with milder COVID-19 cases as well as with other viral pathogens. This hypothesis seems to be true for the vaccines that have been tested in regions where variants are widespread as the overall efficacy is lowered, but the protection from severe disease, hospitalization, and death are still high.
Preliminary reports have suggested that at least part of the increase in transmission of B.1.1.7 emerges from an increased level of virus produced in the upper respiratory tract as well as an increased duration of viral production. To investigate this possible correlation, researchers performed a study between December 1, 2020 and February 20, 2021 in Italy when the B.1.1.7 variant was increasing in prevalence in the country (Calistri et al., 2021). They collected 1,724 COVID-19 samples that were presumed positive for B.1.1.7. From the total samples, 655 had the genome of the virus sequenced to determine the specific variant present, and 313 of the samples were B.1.1.7. Further characterization of the samples indicated that those that were
B.1.1.7 had a statistically significant higher amount of virus compared to samples of the previous variant of SARS-CoV-2. The duration that the RNA-based tests remained positive was also longer for B.1.1.7 compared to the previous variant at 16 days compared to 14 days.
Based on these results, the authors suggest that B.1.1.7 persists longer in the respiratory tract of infected individuals and reaches higher RNA levels compared to those of other SARS-CoV-2 variants.
While several research groups have found that antibodies from early versions of SARS-CoV-2 are less effective against B.1.351, researchers have now reported that antibodies produced after infection with B.1.351 are effective in neutralizing the early version of the virus and P.1 (Moyo-Gwete et al., 2021). The researchers evaluated the antibodies in convalescent plasma from individuals who had recovered from infection with B.1.351, and there was a high level of cross-reactivity from these antibodies with virus from the earlier in the pandemic. The convalescent plasma was also able to neutralize P.1.
The authors suggest that vaccines and therapeutic antibodies designed based on individuals recovered from infection with B.1.351 should allow for production of therapeutics that are effective against all of the currently known variants.
COVID-19 Transmission Updates
Risks in Older Individuals
Researchers have found that cases of re-infection with SARS-CoV-2 have been rare so far during the pandemic, but they occur more often in older individuals (Hansen et al., 2021). The study occurred in Denmark and investigated the rate of re-infection that occurred between the first large surge of transmission between March and May of 2020 and the second surge in transmission between September 1 and December 21, 2020.
During the first surge, 533,381 individuals were tested and 2.2% (11,727 people) received a positive test. During the second surge, 72 of the 11,727 who tested positive during the first surge tested positive again, which corresponds to 0.65%. Of the individuals who had tested negative during the first surge, 16,819 tested positive during the second surge, or 3.27%.
Based on this evaluation, protection against repeat infection for the entire study group was 80.5%.
However, for older individuals, the observed protection against repeat infection was reduced compared to the entire group.
In participants aged 65 years and older, the protection was only 47.1%.
There was no difference in the magnitude of protection based on sex, and there was no evidence of a reduction in protection compared to values calculated at three to six months or at longer than seven months.
Differences in transmission of the virus from close contacts have also been observed for older individuals (Poletti et al., 2021). In a study in Italy, researchers observed 5,484 individuals quarantined after close contact with someone with COVID-19 between the dates of February 20 and April 16, 2020. Individuals in quarantine were monitored daily for symptoms and tested with PCR-based testing and antibody testing.
In total, 51.5% of the group tested positive for COVID-19. Among participants younger than 20 years, the proportion of infected persons who developed symptoms was 18.1%, and 26.1% of infected individuals under the age of 60 developed respiratory symptoms or a fever. The proportion of individuals over the age of 80 who developed symptoms was 64.6%.
Older individuals were also more likely to have more severe symptoms with 6.6% of participants over the age of 60 developed critical disease compared to 0.54% of participants younger than 60 years who developed critical disease.
Additionally, the sex of the individual also influenced the risk of severe disease, and women were 52.7% less likely to develop critical disease than men.
The results of the study confirm the early observations of increased severity of disease with age and also present an explanation on the difficulty in determining a precise proportion of asymptomatic infections as it appears to vary greatly with age.
Effect of Community Mitigation Measures on Transmission
Based on the knowledge that the virus is transmitted predominantly by inhaling respiratory droplets from infected persons, universal mask use can help reduce transmission as stated by researchers at the CDC (Guy et al., 2021). It has also been determined that limiting person-to- person interactions in shared spaces, such as restaurants, where interactions between those not wearing masks and physical distancing are difficult to maintain, can also decrease transmission. Evidence of this effect was investigated by examining the number of COVID-19 cases and deaths between March and December of 2020 as 39 states and the District of Columbia went from prohibiting any on-premises dining at restaurants between March and April but then lifted the bans by mid-June.
During the study, state-issued mask mandates applied in 2,313, or 73.6%, of the 3,142 counties in the United States. Within the first 20 days after implementation, mask mandates led to a 0.5 percentage point decrease in daily COVID-19 case growth rates. The magnitude of the decrease in cases increased as the time from the mandate increased with a final 1.8 percentage point decrease in daily COVID-19 case growth rates 81 to 100 days after the start of the mandate. There was also a decrease in the daily COVID-19 death growth rates, 0.7 percentage points one to 20 days after the inception of the rule increasing to a 1.9 percentage point decrease 81 to 100 days after the mandate’s start.
During the study period, 97% of counties allowed restaurants to reopen for on-premises dining. In the first 40 days after allowing reopening, there was no change in daily COVID-19 case and death rates. However, in the time period between 41 and 60 days after restaurants were allowed to reopen, there was a 0.9 percentage point increase in the case growth rate. The increase continued until the end of the study with a 1.2 percentage point increase in the case growth rate 61 to 80 days after restaurants opened and 1.1 percentage point increase in the case growth rate 81 and 100 days after they opened. Deaths from COVID-19 lag behind an increase in cases, and the researchers found that allowing on-premises dining at restaurants was associated with 2.2 percentage point increase in the death growth rate 61 to 80 days after restrictions were lifted and 3.0 percentage points 81 to 100 days after restrictions were lifted.
Based on the analysis, implementing mask mandates was associated with reduced SARS-CoV-2 transmission within 20 days of implementation, whereas reopening restaurants for on-premises dining was associated with increased transmission and deaths within 41 to 80 days after reopening.
Use of both measures are needed to prevent transmission of COVID-19 in a community until sufficient levels of individuals are vaccinated.
Social Distancing in School
Researchers have investigated if there is a difference in the level of transmission in schools depending on the use of six feet distancing rules or three feet distancing rules (van den Berg, et al., 2021). The recommendation from the WHO is to maintain one meter (3.3 feet) or more while the CDC recommends distancing students six feet or more from each other while at school.
During the 16-week study period, 537,336 students and 99,390 staff attended in-person instruction at 251 eligible school districts in Massachusetts. In all the schools included, universal masking was required. The rate of COVID-19 cases were similar in students and staff in the schools that kept greater than three feet of distance between students and those that kept greater than six feet of distance between students.
Based on the analysis of the results, the authors conclude that physical distancing policies with lower limits can be adopted in school settings with masking mandates without negatively impacting student or staff safety.
After reviewing the available evidence the CDC announced changes to their recommendations for schools (CDC, 2021).
The CDC continues to recommend six feet of distance between adults in schools and between adults and children in school due to the higher risk of infection in adults and when masks cannot be worn, such as during meal times.
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Achenbach J, Cha AE, Dupree J. After weeks of declining cases, echoes of hot spots emerge in Upper Midwest, New York City area. The Washington Post. Published March 16, 2021.
Accessed March 19, 2021 at https://www.washingtonpost.com/health/2021/03/16/covid-cases- rising-michigan-new-york-city/
Arnold DT et al. Are vaccines safe in patients with Long COVID? A prospective observational study. medRxiv. Published March 12, 2021. Accessed on March 18, 2021 at https://www.medrxiv.org/content/10.1101/2021.03.11.21253225v3
AstraZeneca. AZD1222 US Phase III trial met primary efficacy endpoint in preventing COVID-19 at interim analysis. Published March 22, 2021. Accessed March 22, 2021 at https://www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-us-vaccine-trial- met-primary-endpoint.html
Belluck P. Some Long Covid Patients Feel Much Better After Getting the Vaccine. The New York Times. Published March 17, 2021. Accessed March 18, 2021 at https://www.nytimes.com/2021/03/17/health/coronavirus-patients-and-vaccine-effects.html
Blumenthal KG, Robinson LB, Camargo CA Jr, Shenoy ES, Banerji A, Landman AB, Wickner P. Acute Allergic Reactions to mRNA COVID-19 Vaccines. JAMA. 2021 Mar 8. doi: 10.1001/jama.2021.3976. Epub ahead of print. PMID: 33683290.
Britton A, Jacobs Slifka KM, Edens C, Nanduri SA, Bart SM, Shang N, Harizaj A, Armstrong J, Xu K, Ehrlich HY, Soda E, Derado G, Verani JR, Schrag SJ, Jernigan JA, Leung VH, Parikh S. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks – Connecticut, December 2020-February 2021. MMWR Morb Mortal Wkly Rep. 2021 Mar 19;70(11):396-401. doi: 10.15585/mmwr.mm7011e3. PMID: 33735160.
Calistri P, Amato L, Puglia I, Cito F, Di Giuseppe A, Danzetta ML, Morelli D, Di Domenico M, Caporale M, Scialabba S, Portanti O, Curini V, Perletta F, Cammà C, Ancora M, Savini G, Migliorati G, D’Alterio N, Lorusso A. Infection sustained by lineage B.1.1.7 of SARS-CoV-2 is characterised by longer persistence and higher viral RNA loads in nasopharyngeal swabs. Int J Infect Dis. 2021 Mar 5:S1201-9712(21)00210-1. doi: 10.1016/j.ijid.2021.03.005. Epub ahead of print. PMID: 33684558; PMCID: PMC7934691.
CDC. CDC Updates Operational Strategy for K-12 Schools to Reflect New Evidence on Physical Distance in Classrooms. Published March 19, 2021. Accessed on March 22, 2021 at https://www.cdc.gov/media/releases/2021/p0319-new-evidence-classroom-physical- distance.html
Chen X, Chen Z, Azman AS, Deng X, Sun R, Zhao Z, Zheng N, Chen X, Lu W, Zhuang T, Yang J, Viboud C, Ajelli M, Leung DT, Yu H. Serological evidence of human infection with SARS- CoV-2: a systematic review and meta-analysis. Lancet Glob Health. 2021 Mar 8:S2214- 109X(21)00026-7. doi: 10.1016/S2214-109X(21)00026-7. Epub ahead of print. PMID: 33705690.
Chow JH, Khanna AK, Kethireddy S, Yamane D, Levine A, Jackson AM, McCurdy MT, Tabatabai A, Kumar G, Park P, Benjenk I, Menaker J, Ahmed N, Glidewell E, Presutto E, Cain S, Haridasa N, Field W, Fowler JG, Trinh D, Johnson KN, Kaur A, Lee A, Sebastian K, Ulrich A, Peña S, Carpenter R, Sudhakar S, Uppal P, Fedeles BT, Sachs A, Dahbour L, Teeter W, Tanaka K, Galvagno SM, Herr DL, Scalea TM, Mazzeffi MA. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesth Analg. 2021 Apr 1;132(4):930- 941. doi: 10.1213/ANE.0000000000005292. PMID: 33093359.
Centers for Medicare and Medicaid Services. CMS Updates Nursing Home Guidance with Revised Visitation Recommendations. Published March 10, 2021. Accessed March 16, 2021 at https://www.cms.gov/newsroom/press-releases/cms-updates-nursing-home-guidance-revised- visitation-recommendations
Garcia-Beltran WF, Lam EC, St Denis K, Nitido AD, Garcia ZH, Hauser BM, Feldman J, Pavlovic MN, Gregory DJ, Poznansky MC, Sigal A, Schmidt AG, Iafrate AJ, Naranbhai V, Balazs AB. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell. 2021 Mar 12:S0092-8674(21)00298-1. doi: 10.1016/j.cell.2021.03.013. Epub ahead of print. PMID: 33743213; PMCID: PMC7953441.
Guy GP Jr, Lee FC, Sunshine G, McCord R, Howard-Williams M, Kompaniyets L, Dunphy C, Gakh M, Weber R, Sauber-Schatz E, Omura JD, Massetti GM; CDC COVID-19 Response Team, Mitigation Policy Analysis Unit; CDC Public Health Law Program. Association of State- Issued Mask Mandates and Allowing On-Premises Restaurant Dining with County-Level COVID-19 Case and Death Growth Rates – United States, March 1-December 31, 2020.
MMWR Morb Mortal Wkly Rep. 2021 Mar 12;70(10):350-354. doi: 10.15585/mmwr.mm7010e3. PMID: 33705364.
Hansen CH, Michlmayr D, Gubbels SM, Mølbak K, Ethelberg S. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet. 2021 Mar 17:S0140-6736(21)00575-4. doi: 10.1016/S0140-6736(21)00575-4. Epub ahead of print. PMID: 33743221; PMCID: PMC7969130.
Huang Y et al. COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long- Hauler: Looking for Clarity in the Haze of the Pandemic. medRxiv. Published March 5, 2021. Accessed March 16, 2021 at https://www.medrxiv.org/content/10.1101/2021.03.03.21252086v1
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, Padayachee SD, Dheda K, Barnabas SL, Bhorat QE, Briner C, Kwatra G, Ahmed K, Aley P, Bhikha S, Bhiman JN, Bhorat AE, du Plessis J, Esmail A, Groenewald M, Horne E, Hwa SH, Jose A, Lambe T, Laubscher M, Malahleha M, Masenya M, Masilela M, McKenzie S, Molapo K, Moultrie A, Oelofse S, Patel F, Pillay S, Rhead S, Rodel H, Rossouw L, Taoushanis C, Tegally H, Thombrayil A, van Eck S, Wibmer CK, Durham NM, Kelly EJ, Villafana TL, Gilbert S, Pollard AJ, de Oliveira T, Moore PL, Sigal A, Izu A; NGS-SA Group Wits–VIDA COVID Group. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021 Mar 16. doi: 10.1056/NEJMoa2102214. Epub ahead of print. PMID: 33725432.
Moyer MW. Women Report Worse Side Effects After a Covid Vaccine. The New York Times. Published March 8, 2021. Accessed March 9, 2021 at https://www.nytimes.com/2021/03/08/health/vaccine-side-effects-women-men.html
Moyo-Gwete T, Madzivhandila M, Makhado Z, Ayres F, Mhlanga D, Oosthuysen B, Lambson BE, Kgagudi P, Tegally H, Iranzadeh A, Doolabh D, Tyers L, Chinhoyi LR, Mennen M, Skelm S, Wibmer CK, Bhiman JN, Ueckermann V, Rossouw T, Boswell M, de Oliveira T, Williamson C, Burgers WA, Ntusi N, Morris L, Moore PL. SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies. bioRxiv [Preprint]. 2021 Mar 6:2021.03.06.434193. doi: 10.1101/2021.03.06.434193. PMID: 33688657; PMCID: PMC7941631.
NIH. NIH halts trial of COVID-19 convalescent plasma in emergency department patients with mild symptoms. Published March 2, 2021. Accessed March 9, 2021 at https://www.nih.gov/news-events/news-releases/nih-halts-trial-covid-19-convalescent-plasma- emergency-department-patients-mild-symptoms
Novavax. Novavax Confirms high levels of efficacy against original and variant COVID-19 strains in United Kingdom and South Africa Trials. Published March 11, 2021. Accessed March 15, 2021 at https://ir.novavax.com/news-releases/news-release-details/novavax-confirms-high- levels-efficacy-against-original-and-0
Pfizer. Real-world evidence confirms high effectiveness of Pfizer-BioNTech COVID-19 vaccine and profound public health impact of vaccination one year after pandemic declared. Published March 11, 2021. Accessed March 16, 2021 at https://www.pfizer.com/news/press-release/press- release-detail/real-world-evidence-confirms-high-effectiveness-pfizer
Poletti P, Tirani M, Cereda D, Trentini F, Guzzetta G, Sabatino G, Marziano V, Castrofino A, Grosso F, Del Castillo G, Piccarreta R, Andreassi A, Melegaro A, Gramegna M, Ajelli M, Merler S; ATS Lombardy COVID-19 Task Force. Association of Age With Likelihood of Developing Symptoms and Critical Disease Among Close Contacts Exposed to Patients With Confirmed SARS-CoV-2 Infection in Italy. JAMA Netw Open. 2021 Mar 1;4(3):e211085. doi: 10.1001/jamanetworkopen.2021.1085. PMID: 33688964.
Soucheray S. CDC IDs new COVID-19 variants of concern as hotspots reemerge. CIDRAP News. Published March 17, 2021. Accessed March 18, 2021 at https://www.cidrap.umn.edu/news-perspective/2021/03/cdc-ids-new-covid-19-variants-concern- hot-spots-reemerge
Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E, Modat M, Jorge Cardoso M, May A, Ganesh S, Davies R, Nguyen LH, Drew DA, Astley CM, Joshi AD, Merino J, Tsereteli N, Fall T, Gomez MF, Duncan EL, Menni C, Williams FMK, Franks PW, Chan AT, Wolf J, Ourselin S, Spector T, Steves CJ. Attributes and predictors of long COVID. Nat Med. 2021 Mar 10. doi: 10.1038/s41591-021- 01292-y. Epub ahead of print. PMID: 33692530.
Tande AJ, Pollock BD, Shah ND, Farrugia G, Virk A, Swift M, Breeher L, Binnicker M, Berbari EF. Impact of the COVID-19 Vaccine on Asymptomatic Infection Among Patients Undergoing Pre-Procedural COVID-19 Molecular Screening. Clin Infect Dis. 2021 Mar 10:ciab229. doi: 10.1093/cid/ciab229. Epub ahead of print. PMID: 33704435.
Tarke A, Sidney J, Methot N, Zhang Y, Dan JM, Goodwin B, Rubiro P, Sutherland A, da Silva Antunes R, Frazier A, Rawlings SA, Smith DM, Peters B, Scheuermann RH, Weiskopf D, Crotty S, Grifoni A, Sette A. Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv [Preprint]. 2021 Mar 1:2021.02.27.433180. doi: 10.1101/2021.02.27.433180. PMID: 33688655; PMCID: PMC7941626.
Van Beusekom M. Very few severe allergic reactions tied to mRNA COVID vaccines. CIDRAP News. Published March 9, 2021. Accessed on March 10, 2021 at https://www.cidrap.umn.edu/news-perspective/2021/03/very-few-severe-allergic-reactions-tied- mrna-covid-vaccines
van den Berg P, Schechter-Perkins EM, Jack RS, Epshtein I, Nelson R, Oster E, Branch- Elliman W. Effectiveness of three versus six feet of physical distancing for controlling spread of COVID-19 among primary and secondary students and staff: A retrospective, state-wide cohort study. Clin Infect Dis. 2021 Mar 10:ciab230. doi: 10.1093/cid/ciab230. Epub ahead of print. PMID: 33704422.
Vogel G, Kupferschmidt K. ‘It’s a very special picture.’ Why vaccine safety experts put the brakes on AstraZeneca’s COVID-19 vaccine. Science. Published March 17, 2021. Accessed March 18, 2021 at https://www.sciencemag.org/news/2021/03/it-s-very-special-picture-why- vaccine-safety-experts-put-brakes-astrazeneca-s-covid-19
Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, Wang M, Yu J, Zhang B, Kwong PD, Graham BS, Mascola JR, Chang JY, Yin MT, Sobieszczyk M, Kyratsous CA, Shapiro L, Sheng Z, Huang Y, Ho DD. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature. 2021 Mar 8. doi: 10.1038/s41586-021-03398-2. Epub ahead of print. PMID: 33684923.
WHO. Statement of the WHO Global Advisory Committee on Vaccine Safety (GACVS) COVID- 19 subcommittee on safety signals related to the AstraZeneca COVID-19 vaccine. Published March 19, 2021. Accessed March 22, 2021 at https://www.who.int/news/item/19-03-2021- statement-of-the-who-global-advisory-committee-on-vaccine-safety-(gacvs)-covid-19- subcommittee-on-safety-signals-related-to-the-astrazeneca-covid-19-vaccine
Writing Committee for the COMEBAC Study Group, Morin L, Savale L, Pham T, Colle R, Figueiredo S, Harrois A, Gasnier M, Lecoq AL, Meyrignac O, Noel N, Baudry E, Bellin MF, Beurnier A, Choucha W, Corruble E, Dortet L, Hardy-Leger I, Radiguer F, Sportouch S, Verny C, Wyplosz B, Zaidan M, Becquemont L, Montani D, Monnet X. Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19. JAMA. 2021 Mar 17. doi: 10.1001/jama.2021.3331. Epub ahead of print. PMID: 33729425.
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