The epidemic –now pandemic– of the new coronavirus is advancing at a staggering pace. Fortunately, the scientific studies and evidence on the virus (SARS-CoV-2) and the disease (COVID-19) are also advancing at great speed.
In this section, which we will regularly update, we will summarise the most relevant emerging information on SARS-CoV-2.
[Evidence published between 28/04/2021 and 04/05/2021]
An extensive review of more than 30 studies suggests that saliva is as sensitive as nasopharyngeal swabs for PCR-mediated SARS-CoV-2 detection, and much less costly. Thus, saliva samples could replace nasal swabs in most populations being tested.
A study in England shows that regular testing of a random population within the community can quickly detect SARS-CoV-2 outbreaks even if the number of infections is low. This surveillance at the community level could speed up public health responses.
Zooming in on COVID pathology
Several studies published this week look at the single cell level to get a better overall picture of the damage caused by SARS-CoV-2 infection. One study found profound alterations in different cell types obtained from the lung of people who died from COVID-19. Another study analysed single cells beyond the lung (kidney, liver, and heart and found similar results, while experiments with “intestines in a dish” showed that SARS-Cov-2 infection interfered with the immune response in the gut. Another single-cell study focusing on cerebral spine fluid identified SARS-CoV-2 antibodies that can also target neural antigens, suggesting that the neurologic sequalae of COVID-19 may have an autoimmune origin.
Behind the loss of smell
The loss of smell in many patients may be the results of virus that infects and persists in the human olfactory epithelium, which may in turn lead to prolonged inflammation, according to a study.
Obesity: risk confirmed
A study in the US found that, at a body mass index (BMI) above 23, there is a linear increase in COVID-19 hospitalisation and death. The risk was particularly notable in people younger than 40 years and in people of Black ethnicity. Another study with over 70,000 patients in Mexico shows that obesity alone increased almost three-fold the risk of dying of COVID-19. Having other diseases such as diabetes increased the risk even further.
A select group of superneutralisers
A study in convalescent individuals shows a large variation in the capacity of their antibodies to neutralise the SARS-CoV-2 virus. Around 3% were “superneutralisers”, 21% were high neutralizers, 45% were average, 10% were low and 20% were non-neutralisers.
One dose, two doses
An analysis by the US CDC shows that one vaccine dose decreased hospitalisation of adults above 65 years by 64%, while both doses (full vaccination) decreased it by 94%.
A study with healthcare workers shows that individuals who were previously infected produce neutralizing antibodies that are effective against B.1.1.7 (“British”) and B.1.351 (“South African”) variants after one vaccine dose. In contrast, healthcare workers without history of infection showed reduced immunity against these variants after one single dose, confirming the need for two doses in these individuals.
According to a modelling study, one-dose strategies may reduce infections in the short term but may increase the potential for viral evolution if the immune responses are suboptimal and the virus continues to replicate in some vaccinated people.
Vaccines and transmission: much-awaited results
A study in England shows that one single dose of the Pfizer or AstraZeneca vaccines can cut household transmission by 50%. The study was the first to follow household contacts of infected individuals who were previously vaccinated or not.
[Evidence published between 22/04/2021 and 27/04/2021]
Transmission and children
A study of household transmission in Wuhan suggests that children and adolescents are less susceptible to SARS-CoV-2 infection but more infectious than older individuals. The findings also indicate that people are most infectious before developing symptoms (presymptomatic), but those who do not develop symptoms (asymptomatic) are less infectious than those who do.
In the absence of vaccines for children, the rapid identification of silent infections among kids will be key to breaking transmission chains, according to a modelling study with simulations.
The largest study to date, with over 70,000 hospitalised and 13,000 non-hospitalised COVID-19 patients, shows these patients suffer from several sequalae beyond the first 30 days of illness. These include respiratory, neurocognitive, gastrointestinal, cardiovascular, and mental health disorders, as well as fatigue, muscle pain and anemia. The risk of post-covid sequelae was highest among those with severe disease.
T cells lead the way
A study (not yet peer-reviewed) shows that T cell responses almost reach their maximal level already after the first vaccine dose, while antibodies need two doses to reach maximal levels. In fact, the magnitude of the CD4 T cell response after the first dose predicted the levels of CD8 T cells and neutralizing antibodies after the second dose.
A super antibody?
The analysis of a large number of B cells (which produce antibodies) from COVID-19 patients identified a series of potently neutralizing antibodies targeting the Spike protein. One of these antibodies was capable of fully neutralising the original SARS-CoV-2, the B.1.1.7 and B.1.351 variants, and even SARS-CoV. These antibodies could help design future treatments and vaccines with broad effect against coronaviruses.
One dose for previously-infected people
Yet another study shows that one vaccine dose is enough for previously-infected individuals. Naïve individuals required both vaccine doses for optimal increases in antibodies, particularly for neutralizing titers against the B.1.351 variant. In recovered individuals, antibody and memory B cell responses were significantly boosted after the first vaccine dose and did not increase after the second dose.
Vaccines and pregnancy
Preliminary findings of a study with 35,691 pregnant participants do not show any safety signals among pregnant persons who received mRNA Covid-19 vaccines.
More clues on the rare cases of thrombosis
The German team that first studied the thrombosis cases associated to the AstraZeneca vaccine provides further evidence on the possible mechanisms. Certain non-viral vaccine components related to the vaccine fabrication process may be favouring the production of antibodies that activate the platelets and trigger the thrombotic events. The paper has not yet been peer-reviewed.
1 billion doses and a stark gap
Only 15 months after the pandemic started, more than 1 billion (1000, 000, 000) vaccine doses have been administered worldwide. However, almost 9 out of 10 have been administered in high and upper middle-income countries. Only 0.2% of these doses have reached the poorest countries.
[Evidence published between 14/04/2021 and 21/04/2021]
This week, the world surpassed 3 million COVID-19 deaths.
Innocent until proven guilty
Another variant first identified in India (B.1.617) has raised some alarm because it presents two mutations in Spike (E484Q and L452R) that have shown evidence of antibody escape in the laboratory. But there is no evidence yet that the variant is more transmissible or can escape immunity. This variant deserves close monitoring but is not cause for concern, experts say.
Antibodies obtained from a convalescent COVID-19 patient were found to neutralise multiple SARS-CoV2 variants of concern and SARS. A team from Scripps Institute identifies the binding sites that facilitate cross-reactivity of these antibodies. These findings provide valuable information for designing vaccines and therapeutic antibodies against current and future SARS-related viruses
Lower risk of reinfection
A study with young, healthy US Marine recruits shows that seropositive individuals (i.e. with antibodies to SARS-CoV-2) had about one fifth the risk of subsequent infection as compared with seronegative individuals (10% vs 48%). Furthermore, infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants, meaning they are less likely to transmit.
More on vaccines
Data from Chile
Chile has announced that Sinovac’s vaccine is 80% effective against death and 67% effective against COVID-19 symptoms. Protection after one single dose was much lower. Almost 34% of the country’s population has been fully vaccinated, 93% of which have received the CoronaVac vaccine.
Responses in older people
Single doses of either the Pfizer of the Oxford / AstraZeneca vaccine in older people induce humoral immunity (antibodies) in most donors and are greatly enhanced in those who had a previous infection, according to a study (not yet peer-reviewed) in the UK. Cellular responses (T cells) are weaker but overall better with the AstraZeneca jab.
Yes, vaccines work!
The US CDC has identified some 5,800 cases of SARS-Cov-2 infection among more than 66 million fully vaccinated Americans. These “breakthrough” cases, which are defined as positive PCR results at least two weeks after patients the second dose, represent 0.008% of the fully vaccinated population. 7% of these infections (i.e. 0.00056%) needed hospitalization and only 7 fully vaccinated people died (0.00001%).
Meanwhile, a study on the effects of vaccination among nursing home residents, staff and healthcare workers in Catalonia shows an 85%-96% reduction in SARS-CoV-2 infection in all three cohorts, and even bigger reductions (>95%) in hospitalisations and mortality amongst nursing home residents for up to two months.
A pan-coronavirus vaccine?
Developing a vaccine capable of protecting against known and unknown coronaviruses (at least those pertaining to the beta coronavirus family) is possible, and has suddenly become a top priority. Many teams are currently using different strategies to achieve this goal.
Rare thrombosis cases
EMA’s safety committee concluded that the unusual thrombosis cases linked to the Johnson & Johnson vaccine were very similar to those observed with the AstraZeneca vaccine and that unusual blood clots with low blood platelets should be listed as very rare side effect of the vaccine. The agency emphasised that the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects.
The first study to examine suicides in the context of the COVID-19 pandemic in several countries found that, in high and upper middle-income countries, suicide numbers remained largely unchanged or declined in the early months of the pandemic. The situation however may change as economic effects are felt.
[Evidence published between 07/04/2021 and 13/04/2021]
Neurological and psychological sequelae
A retrospective study with almost 250,000 COVID-19 survivors shows that 33% of them had a neurological or psychiatric diagnosis in the following 6 months, particularly those who had severe COVID-19. However, almost 90% of these patients had already received a neurological or psychological diagnosis before COVID-19, and the reported symptoms ranged from dementia and stroke to anxiety and insomnia.
Protection by natural immunity
A follow-up study with over 25,000 health care workers in England shows that those with a previous history of SARS-CoV-2 infection had an 84% lower risk of infection and a 93% reduction in symptomatic infections for at least 7 months.
Protection against variants
Yet another study shows that sera from convalescent individuals collected up to 9 months after symptoms effectively neutralized the dominant (D614G) and the B.1.1.7 variants, but had reduced or no activity against B.1.351. Similar results were observed with sera from vaccinated individuals. These results indicate that B.1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.
Good news on treatments
Avoiding COVID-19 with antibody cocktails
Regeneron announced that its monoclonal antibody cocktail reduced by 81% the risk of developing COVID-19 after exposure. The study enrolled 1,500 healthy volunteers, each of whom shared a home with someone who tested positive for SARS-CoV-2. The mAb cocktail was given subcutaneously (instead of intravenously). In those who did develop the disease despite treatment, the symptoms resolved after one week, compared to three weeks for those on placebo.
Early treatment with an asthma drug
In a small controlled trial in the UK, patients were given budesonide (an inhaled corticosteroid commonly used for asthma) within 7 days of developing mild symptoms. Treated patients showed a significant reduction of clinical deterioration and reduced time to recovery as compared to the placebo group. In another, larger, clinical trial which involved more than 1,700 people at high risk (above 50 or 60 years of age), two daily inhalations of the drug also helped people at home recover more quickly from COVID-19. The results have not yet been peer-reviewed.
More on vaccines
The French pharmaceutical company Valneva reported positive phase 2 data for its COVID-19 vaccine candidate based on inactivated virus particles: it was well tolerated and induced neutralising antibody titres at or above levels seen in convalescent sera, as well as broad T cell responses. It plans to launch a phase 3 trial by end of April.
A study in Israel (not yet peer-reviewed) shows that the few infections observed in fully vaccinated people (two doses) were mostly due to the B.1.351 variant (first identified in South Africa), while those infected between the first and second dose were mostly infected by B1.1.7. These results confirm that two doses of the vaccine effectively protect against B1.1.7, and that B1.351 poses more of a risk but its spread can be curbed if mass-vaccination is coupled with non-pharmaceutical interventions.
Sinovac’s inactivated virus vaccine (CoronaVac) shows a 50% efficacy in preventing symptomatic disease but a 100% protection against severe disease, according to data from the clinical trial performed in Brazil. Another study (not yet peer-reviewed) confirms that at least one dose of the vaccine showed 50% effectiveness against symptomatic infection and 35% effectiveness against all infections, in a context where the P1 variant is widely circulating.
Two studies (one in Germany and one in Norway) provide a possible explanation for the rare thrombotic events associated with the AstraZeneca vaccine. In all the cases studied, researchers found antibodies that bind to and activate platelets. The mechanisms leading to the production or the activation of these antibodies are being investigated. Researchers will closely monitor this type of events with the other COVID-19 vaccines based on adenoviral vectors. In fact, the EMA is supporting studies to identify cases, look for potential causes or risk factors, and evaluate whether the risk can be cut by reducing the amount of vaccine administered in each dose.
[Evidence published between 31/03/2021 and 06/04/2021]
An important first step
The WHO-led mission has published its report on the origin of SARS-CoV-2, which contains new information and insights. It concludes that introduction into humans most likely occurred from bats via an intermediate host, that transmission likely started in mid-November but the Huanan market was the amplifier of the outbreak, and that further investigation needs to be done on the origins of the virus. It reiterates that all hypotheses remain open, and that this investigation is only the beginning.
Detecting variants as they emerge
The B1.1.7 variant probably arrived in the U.S. by October of 2020, and was in at least 15 countries before it was first identified in UK, according to an analysis by the University of Texas. An online calculator developed by the team indicates the number of virus samples that must be sequenced in order to detect new variants when they emerge.
Not all transmission is equal
A study in China estimates that 38% of the infections resulted from transmission by individuals with no symptoms. Contacts infected by asymptomatic individuals were more likely to be asymptomatic and less likely to develop severe disease. It also shows that the risk of transmission was higher within households or through shared dining.
No cross-protection in children?
A multicentric study in France suggests that previous infections by seasonal “common cold” coronaviruses do not provide cross-protective immunity against SARS-CoV-2 infection or disease in children.
More on vaccines
Pfizer/BioNTech announced that their Covid-19 vaccine induced robust antibody responses, prevented symptomatic disease, and was well-tolerated in a trial of 2,260 adolescents ages 12 to 15.
And the ongoing phase 3 clinical trial of their vaccine confirms its protection remains high for at least 6 months after the second dose: more than 91% effective against symptomatic disease and 100% effective against severe disease. Furthermore, a small trial in South Africa with 800 participants shows high efficacy against the B1.351 variant (the nine cases were in the placebo group).
A study with individuals vaccinated with the AstraZeneca/Oxford vaccine shows that its efficacy against asymptomatic infection was lower for the B1.1.7 variant (30%) as compared to the original variant (70%).
The rare cases of thromboses seen in recipients that received the AstraZeneca shot may be associated with the vaccine, according to German researchers. This rare side effect may be due to antibodies binding to platelets and activating them, similar to heparin-induced thrombocytopenia.
As many experts point out, it is important to further investigate these cases in order to identify people at risk. Meanwhile, a panel of experts in the UK has published guidance on how to detect and treat the rare possible thrombotic effects of the AZ vaccine.
600 million doses and a wide gap
More than 66o million vaccine doses have been administered worldwide, but there is already a wide gap between countries: 86% of shots have been administered in high and upper-middle income countries and only 0.1% in low-income countries. Covax has shipped 33 million doses to 70 countries (barely 6% of the total doses administered worldwide).
[Evidence published between 24/03/2021 and 30/03/2021]
No spitting, please
A study analysing human salivary glands and gingiva shows that the mouth is an important site for SARS-CoV-2 infection and points to saliva as a route of viral transmission. The amount of virus in saliva correlated with COVID-19 symptoms, including taste loss. Notably, saliva from asymptomatic individuals was also capable of infecting cells in the laboratory.
Digging deeper into Long Covid
A series of studies posted this week (not yet peer-reviewed) provide more information on Long Covid. Two Follow-up studies of COVID-19 patients after being discharged from the hospital in the UK show that, 5 to 7 months later, between 55 and 70% of them had not fully recovered. Being female, middle-age and of white ethnicity were associated with failure to recover.
The most common symptoms of Long Covid were fatigue (79.0%), headache (55.3%), shortness of breath (55.3%), difficulty concentrating (53.6%), cough (49.0%), changed sense of taste (44.9%), diarrhoea (43.9%), and muscle or body aches (43.5%). According to a social media survey, cognitive dysfunction and palpitations became more prevalent later in the illness. Many of these symptoms seem to “come and go”, as in waves.
Vaccines boost natural immunity, even against variants
Sera from recovered individuals neutralize the original variant and, to some degree the B1.351 variant (first identified in South Africa). However, a single dose of mRNA boosted the titers of neutralizing antibodies against all variants, and even against SARS-CoV-1, by up to 1000-fold.
Early evidence that vaccines also prevent infections
A real-field study by the US CDC, with almost 4,ooo healthcare workers vaccinated with the Pfizer or Moderna vaccines, provides evidence that these vaccines not only protect against disease, but are also highly effective in preventing SARS-CoV-2 infection. The risk of infection was reduced by 90% two or more weeks after the second dose of vaccine.
Furthermore, a study in Israel shows that the viral load was substantially reduced in people who were infected 12 to 37 days after the first dose of the vaccine. This suggests that vaccinated people, even if they do get infected, are less likely to spread the virus.
And another study (not yet peer-reviewed) in residents of long-term care facilities in the UK also shows a sharp decline in PCR-positive infections and viral load after the first dose of Pfizer or AstraZeneca vaccines, relative to unvaccinated residents.
Update on AstraZeneca’s US trial
AstraZeneca has updated its US trial results, with a total of 190 cases. Efficacy against symptomatic COVID occurring 15 days or more after two doses given four weeks apart was 76%, and up to 85% in adults 65 years or older. Efficacy against severe or critical disease and hospitalisation was 100% (8 cases, all in placebo group).
mRNA vaccines in pregnant women
A cohort study in two centres indicates that the COVID-19 mRNA vaccines are safe and effective in pregnant and lactating women. With the added advantage that the vaccine-induced antibodies passed from the mother to the baby via the placenta and breastmilk.
[Evidence published between 17/03/2021 and 23/03/2021]
Reinfection data from Denmark
Almost 4 million people have been tested in Denmark’s free-of-charge testing strategy in 2020. An analysis shows that, of those who tested positive for the first surge, 0.7% tested positive again in the second surge, as compared to 3.3% who were negative in the first surge. This means that protection against reinfection was 80·5%. However, it decreased to 47% in people older than 65. Protection did not seem to wane over time (79% at 3 months versus 78%% at 7 months of follow-up).
Seroprevalence data from Wuhan
A longitudinal study in Wuhan (April to December, 2020) with 3600 families shows that 6.9% of the 9,700 individuals tested were positive for SARS-CoV-2 antibodies, and that 82% of antibody-positive individuals were asymptomatic. Neutralising antibodies (detected in 40% of antibody-positive individuals) remained stable for more than 9 months.
An autopsy study reveals that cardiac infection with SARS-CoV-2 is common among patients dying from COVID-19, but often the number of infected cells is low. Cardiac infection was associated with heart inflammation and an altered electrocardiogram.
People infected with the B1.351 variant (first identified in South Africa) produce high titers of antibodies that are effective against the original variant and the P.1 variant (first identified in Brazil), according to a study that has not yet been peer-reviewed. These data suggest that vaccines designed with the B1.351 sequence may provide broad protection against the other variants.
Two other studies suggest that previous infection or vaccination may offer some degree of protection against the B1.351 variant: antibodies from convalescent sera (up to eight months after infection) or sera from individuals vaccinated with the Moderna vaccine were shown to retain neutralising activity against the B1.351 variant.
A boost for the AstraZeneca vaccine
An interim analysis from the US trial of the AstraZeneca / Oxford vaccine, with 32,000 volunteers, confirms it is safe and shows a better than expected efficacy: it reduced symptomatic infections by 79% (from a total of 141 cases) and severe disease by 100% (although the number of severe cases was quite low: a total of 5, all of them in the placebo group). No increased risk of thrombotic events (including cerebral venous thrombosis) was observed. Around 20% of the trial volunteers were over 65 years of age, and the vaccine protected them equally well.
However, in a highly unusual statement, the US NIH expressed concern that AstraZeneca may have included outdated information from the trial.
While Western countries are losing out on vaccine diplomacy (90% of the approx. 400M doses delivered so far have been administered in rich countries), China has produced about a third of the world’s vaccine doses and exported nearly two-thirds of its production to Latin America and other regions.
[Evidence published between 10/03/2021 and 16/03/2021]
News on antibody-based treatments
Eli Lilly announced that its combination therapy with two monoclonal antibodies against SARS-CoV-2 reduced the risk of hospitalization and death by 87% in a study including more than 750 high-risk COVID-19 patients. This combination therapy could offer greater protection against new viral variants, as compared to single monoclonal antibodies.
In contrast, the RECOVERY trial in UK concluded that convalescent plasma containing high titers of antibodies did not decrease mortality within 28 days in treated COVID-19 patients as compared to non-treated ones.
Vaccines and transmission
A study in the US with almost 40,000 adults with no COVID symptoms indicates that COVID-19 vaccines also reduce asymptomatic infections. The risk of testing positive for SARS-CoV-2 was 79% lower 10 days after one dose of the vaccine, and up to 81%% lower among those who had received two doses of the vaccine, as compared to unvaccinated people.
Vaccines and viral variants
A study with “pseudoviruses” expressing mutations in the RBD observed in the new viral variants shows that those in the B1.351 variant (first identified in South Africa) are highly resistant to neutralisation by sera from individuals vaccinated with mRNA vaccines.
However, many researchers believe that, given the antibody concentration elicited by many of the COVID-19 vaccines, there is a reasonable “safety margin” that would still protect people from symptomatic infection, or at least from severe disease.
Accordingly, data from the Novavax trials indicate that the vaccine is effective in preventing severe disease from any strain, including B.1.351 (South Africa), although it is not as effective at preventing milder disease.
Along the same line, a study (not yet peer-reviewed) shows that one single dose of the AstraZeneca / Oxford vaccine protected hamsters against clinical disease caused by the B1.351 variant, despite an almost 10-fold reduction of neutralizing activity.
Vaccines and Long Covid
A small study (not yet peer reviewed) suggests that vaccination (both with the Pfizer and AstraZeneca /Oxford vaccines) is safe in patients with Long COVID and may even alleviate some of their symptoms.
Thrombosis: no causal evidence for the moment
Several European countries have stopped administering the AstraZeneca / Oxford vaccine as precautionary principle, after some cases of thrombosis were reported. However, to date, no causal link has been established between this vaccine and thrombosis. According to the EMA, there have been 30 cases of thrombosis in more than 5 million people who have received the vaccine in the European Union. According to cases reported to the company until March 8, there have been 15 events of deep vein thrombosis and 22 events of pulmonary embolism among more than 17 million people vaccinated in the EU and UK. This is actually lower than the 100 cases per week that would be normally expected in a population of similar size (deep vein thromboses happen to around one person per 1,000 each year).
Preparing for future pandemics
The Coalition for Epidemic Preparedness and Innovation (CEPI) has launched a $3.5 billion plan to combat future pandemics. It is based on three actions:
- Prepare for known pandemic threats (develop vaccines and biologics against the most prominent threats known)
- Transform the response to the next novel threat (disease X) by using rapid response platforms and innovations.
- Connect and enhance global collaboration.
[Evidence published between 03/03/2021 and 09/03/2021]
New on risk factors
Of the 2.5 million COVID-19 deaths reported by the end of February 2021, 2.2 million (88%) occurred in countries where more than half the population is classified as overweight, according to a study by World Obesity Forum. And a study in the US confirms that obesity was a risk factor for hospitalization and death, particularly among adults under 65 years of age.
A study provides a possible molecular explanation for the link between blood group A and higher risk of severe COVID-19. The receptor binding domain of SARS-CoV-2 binds to blood group A antigens that are expressed on respiratory epithelial cells but not on red blood cells.
A retrospective analysis suggests that statin use reduces deaths by COVID-19. The authors compared 648 patients who regularly used statins before developing COVID-19 to 648 matched patients who did not use statins. In-hospital mortality in the first 30 days was 14.8% versus 26.5%. Statins have anti-inflammatory and antithrombotic properties and may influence viral infectivity through effects on lipids on our cell membranes.
Neutrophil activation- predictor of severe disease and death
Two studies point to neutrophil activation as a predictor of critical illness and death. One of them found that patients with an unfavourable outcome displayed a state of increased activation of the innate immune arm, particularly increased neutrophils, at hospital admission. The other found an increase in neutrophil activation markers on the first day of hospitalisation in patients who later on required transfer to the intensive care unit.
Immunity to variants- T cells may save the day
A study using sera from convalescent patients or individuals vaccinated with the Pfizer/ BioNTech vaccine shows a reduced inhibitory activity against viruses containing the E484K spike mutation (present on the variants first identified in South Africa and Brazil).
However, a study (that has not yet been peer reviewed) shows that SARS-CoV-2-specific CD4 and CD8 T cells from convalescent subjects or recipients of the Pfizer or Moderna vaccines are not substantially affected by mutations found in the different variants recently described (B1.1.7, B1.351, P.1 and CAL.20C).
Negative results for a series of repurposed drugs
Two randomised controlled trials report negative results for drugs that block the inflammatory cytokine IL6. One in India comparing tocilizumab versus standard care in patients with moderate to severe COVID-19 showed no benefit in terms of disease progression. The other, a multinational trial with COVID-19 patients who required oxygen supplementation or intensive care, showed no clinical improvement in patients who received sarilumab. Other studies have shown a benefit, but this may depend on the timing of the treatment and whether the patients are also receiving corticosteroids.
A randomized clinical trial in Colombia with 476 patients shows that the antiparasitic drug ivermectin (given during five days 300 ug/kg per day) did not reduce the duration of symptoms as compared to the placebo group. Further controlled clinical trials are needed to recommend- or not- the use of this controversial drug for COVID-19 treatment.
The RECOVERY trial in UK has stopped testing colchicine (used for treating inflammation and pain) for lack of efficacy in patients hospitalised with COVID-19. There was no significant difference in mortality at 28 days.
In turn, the US NIH stopped its trial of early administration of convalescent plasma to prevent COVID-19 progression, due to lack of efficacy.
[Evidence published between 24/02/2021 and 02/03/2021]
Variants: need for clinical evidence
An analysis using serum samples from convalescent patients or from vaccinated people shows that the mutations in the B1.351 variant, first identified in South Africa, can partially escape from antibody-mediated neutralisation. Another study confirms this, but finds no evidence (in the laboratory) of an increased infective capacity.
Other variants identified in California and elsewhere carry another mutation (L425R) that is believed could enhance infectivity or facilitate immune escape. However, additional research is needed to confirm this.
Ultimately, the most valuable information will come from the clinic, when there is a decrease in vaccine efficacy or a propensity for reinfection linked to particular variants.
Long COVID- still puzzling but now a priority
Around one in 10 people who have been infected with the virus are still unwell 12 weeks after, according to a new policy brief by the WHO. The document provides guidelines on how to better diagnose, treat and investigate this condition, which is not yet well understood but can be severely disabling.
Surveillance in settings with limited resources
Infection prevalence in a population can be accurately estimated by pooling samples instead of performing individual tests. A study shows that a prevalence of 1% (i.e. 1 of 100 persons infected) could be accurately estimated from 2,304 pooled samples, using only 48 tests.
With some help from Neanderthals
A new, large genetic association study shows that a genetic variant inherited from Neanderthals could reduce the risk of becoming severely ill with COVID-19 by around 20%. This variant, situated on chromosome 12, encodes for proteins (enzymes) which are involved in fighting RNA viruses. The Neanderthal DNA was passed to humans around 60,000 years (thanks to interbreeding) and has increased in frequency over the last 1000 years. It is now found in up to 50% people living outside Africa.
Antibodies- the top 1%
A study shows that around 1.4% of antibodies isolated from convalescent patients exhibit a highly potent neutralising activity against SARS-CoV-2. One of these antibodies was capable of neutralising the original variant as well as those containing the D614G, E484K and N501Y mutations. It prevented and treated SAR-CoV-2 infection in hamsters
More on vaccines
One more vaccine approved in the US and, hopefully, soon in Europe
The US FDA approved Johnson & Johnson’s vaccine for use in individuals 18 years of age and older. The vaccine uses a viral vector (Ad26) and has the advantage of needing only one dose. The clinical trial results show that, 28 days after the shot, the vaccine was around 70% in preventing symptoms and 100% effective in preventing COVID-19 deaths. Data from the trial suggest that the vaccine also decreased the number of asymptomatic infections.
Pfizer’s vaccine efficacy is confirmed in Israel and the UK
A study with 600,000 vaccinated people in Israel shows that the vaccine’s effectiveness (which means its efficacy in real-life conditions) at 7 or more days after the second dose was 94% for symptomatic COVID-19 and 92% for severe disease. No deaths were observed in the vaccinated group at this timepoint. Vaccine effectiveness was similar for elderly and younger adults.
Another study with more than 20,000 healthcare workers in the UK confirms these results: protection from symptoms was 85% at 7 days or more after the second dose. The study also provides some evidence suggesting that the vaccine may reduce viral transmission by reducing both asymptomatic and symptomatic infections. This study has not yet been peer-reviewed.
[Evidence published between 17/02/2021 and 23/02/2021]
The difference lies in the sugar
Recent evidence suggests that SARS-CoV-2 S protein has a higher binding affinity to the human ACE2 receptor than SARS-CoV-1. A study shows that this is because the SARS-CoV-2 receptor binding domain interacts with a sugar (or glycan) attached to an amino acid (asparagine in position 90) on ACE2. This interaction is absent in the SARS-CoV-1 virus. These results could help develop new strategies to block viral infection.
Viral mutations and monoclonal antibodies
One year after its emergence, the SARS-CoV-2 population has accumulated over 75 mutations, which could have implications not only for vaccines but also for monoclonal antibody-based therapies. In fact, a study mapped how mutations in the receptor binding domain (RBD) may escape recognition by monoclonal antibodies developed by REGENERON and Lilly. The results show that some mutations potentially capable of escaping these individual antibodies are already circulating in the human population.
Underreporting in Africa?
A study performed in a hospital in Zambia suggests that COVID-19 cases and deaths have been under-reported because testing was rarely done. SARS-CoV-2 was detected in 16% of 400 deceased people in whom postmortem nasopharyngeal swabs were analysed. Although the number of confirmed COVID-19 deaths in the African continent represents a small fraction of those reported globally, the death toll has been rising fast, reaching 100,000 confirmed deaths.
20 million years of life lost to COVID-19
Over 20.5 million years of life may have been lost due to COVID-19 globally, with an average of 16 years lost per death, according to a study across 81 countries. In heavily affected countries, this means 2-9 times the average seasonal influenza. Three quarters of the years of life lost result from deaths below 75. Men have lost 45% more life years than women.
Inhibition of interferon alpha signalling
Patients with severe COVID-19 produce antibodies that block a functional response to interferon alpha, one of our first lines of antiviral defence. The study compared gene expression in a wide variety of immune cells from patients with mild or severe COVID-19.
Long-lived memory B cells
Another study in patients recovered from mild to moderate COVID-19 supports long-lived immunity to SARS-CoV-2: although a decline in antibodies is observed over the first 4 months post-infection, virus-specific memory B cells consistently accumulate over time.
An intranasal lipopeptide
Intranasal administration of a lipopeptide that inhibits the fusion between the viral and cell membranes completely prevented viral transmission in ferrets. These lipopeptides are highly stable and may represent a safe and effective prophylaxis to reduce transmission of SARS-CoV-2.
More data on approved vaccines
Longer intervals between doses for Oxford vaccine
A pooled analysis of the Oxford vaccine shows that efficacy was higher among those with a longer interval between the two doses (81.3% with a 12-week interval versus 55% with an interval under 6 weeks). There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after 21 days of the first shot, versus 15 in the control group.
Protection after the first dose of the Pfizer vaccine
A study comparing vaccinated and unvaccinated health care workers in Israel shows that the rate of reduction of SARS-CoV-2 infections among the former was 30% (days 1-14) and 75% (days 15-28) after the first dose. However, it is not known how long protection lasts following one single dose.
Protection against hospitalisation
Preliminary results from Scotland suggest that both the Pfizer/BioNTech and the Oxford/AZ vaccines protect against severe infections. The showed that, by the fourth week after the initial dose, the risk of hospitalisation among people over 80 years of age was reduced between 85% and 94%. In total, there were just over 8,000 people who ended up in hospital, and only 58 were among the vaccinated group. These results have not yet been peer-reviewed. In turn, Israel announced that the Pfizer vaccine has an efficacy of 98.9% in preventing hospitalization and deaths by COVID-19.
[Evidence published between 10/02/2021 and 16/02/2021]
More on its origin
The emergence of SARS and SARS-CoV-2 could be the direct consequence of climate change that led to shifts in bat distribution in the Chinese Yunnan province and neighbouring regions, according to a study.
In fact, bats that harbour coronaviruses related to SARS-CoV-2 show an extended geographic distribution from Japan and China to Thailand, over a 4800-km range.
In turn, the WHO-led mission that recently visited China has concluded that the “jump” from bats to humans likely involved an intermediary host such as rabbits, ferrets or bamboo rats, which are susceptible to the virus and were sold at the Wuhan market.
Another risk factor?
Low birth-weight has been identified as an independent risk factor for severe COVID-19 in adults under 70 years of age, according to the follow-up of almost 400 patients at the Hospital Clinic in Barcelona.
No cross-protection by common colds?
Many people possessed cross-reactive SARS-Cov-2 antibodies before the pandemic as a result of infections by human cold coronaviruses. A study shows that although these antibodies are boosted upon SARS-CoV-2 infection, they are not protective.
Breastfeeding and COVID-19
A study that analysed milk samples from women diagnosed with COVID-19 shows that none of the milk samples contained the virus, but 80% contained anti-SARS-CoV-2 IgA and/or IgG antibodies. In addition, 62% of milk samples were able to neutralise the virus in the laboratory. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19.
A rheumatoid arthritis drug
The RECOVERY trial in UK has presented data showing that the tocilizumab (an antibody that blocks the inflammatory IL6 cytokine) significantly reduces the risk of death when given to hospitalised patients with severe COVID-19: 29% of the patients treated with tocilizumab and dexamethasone died within 28 days, compared with 33% of those treated with dexamethasone alone. Tocilizumab also shortened the time until patients were successfully discharged from hospital and reduced the need for a mechanical ventilator.
The analysis of a nationwide cohort of COVID-19 patients in the US shows that early initiation of blood thinners among patients admitted to hospital with COVID-19 was associated with a decreased risk of mortality after 30 days and no increased risk of serious bleeding events.
Camel-derived antibodies (or nanobodies) are smaller than human antibodies and therefore easier to produce and administer. Researchers have engineered nanobodies that simultaneously target distinct epitopes of the SARS-CoV-2 spike protein. These multivalent nanobodies are much more potent in neutralising the virus and could work against different viral variants.
In fact, it should be possible to develop antibodies and pan-virus vaccines, capable of recognising a large variety of coronaviruses, say several experts.
Anaphylaxis related to mRNA vaccines
To date, 66 cases of anaphylaxis have been reported in the US, out of 18 million vaccinations with mRNA vaccines (0.0003%). All but 1 occurred within the first 11 minutes, and there were no deaths.
Good signs from Israel
In Israel, 90% of adults over 60 years-old have received one or two doses of the Pfizer vaccine, and the results are starting to show.
The country has seen a 94% drop in symptomatic COVID-19 infections among 600,000 people who received two doses of the Pfizer mRNA vaccine. The same group was 92% less likely to develop severe illness.
Furthermore, preliminary results show a significant decrease in viral load among people over 60 years of age, one month after the vaccination rollout started in this age group. This suggests that vaccination may also impact on transmission.
[Evidence published between 03/02/2021 and 09/02/2021]
Latest news on variants
A further analysis of the AstraZeneca/Oxford vaccine trial indicates that, although vaccine-induced antibodies were less effective in neutralising the B1.1.7 variant in the laboratory, vaccine efficacy against symptomatic infections caused by the variant was only slightly lower (75% vs 84%).
However, a small trial with 2,000 people in South Africa shows that the same vaccine offered almost no protection against mild and moderate disease caused by the B1.3.5 variant. Experts still hope it will protect against hospitalisation and death, but authorities have decided to stop rolling out the AstraZeneca vaccine and roll out the Johnson and Johnson vaccine instead, until more data are available.
Scientists in the UK reported that a small number of B1.1.7 variants have developed the E484K mutation, which is also found in variants in Brazil and South Africa and may help SARS-CoV-2 partly evade immunity.
Transmission: getting a grip on the who, when, and how
An analysis performed in the US concludes that at least 65% of SARS-CoV-2 infections originated from individuals aged 20-49.
Another analysis of 282 COVID-19 clusters in Catalonia shows that the viral load was a leading driver of SARS-CoV-2 transmission. People with low viral load infected 12% of their contacts, while people with high viral load infected 24% of their contacts.
A study that followed 655 hospitalised patients in France concludes that the peak in viral load occurs in average one day before symptom onset and that the decline in viral load is slower in older patients. It also confirms that the dynamics of viral load after hospital admission is a predictor of the risk of death.
Another follow-up study with over 200 patients shows that around 5% were persistently PCR-positive after 90 days. However, transmission to close contacts was not observed, indicating that these individuals are not contagious at the post-symptomatic stage of the infection.
It is now clear that SARS-CoV-2 is transmitted predominantly through the air, by people talking and breathing out large droplets and aerosols. In contrast, catching the virus by touching infected surfaces seems to be rare.
Interferon lambda-1 is a small molecule involved in the innate response against respiratory pathogens. A small trial with non-hospitalised COVID-19 patients shows that a subcutaneous injection of this molecule resulted in lower viral loads in treated patients as compared with the placebo group.
Researchers used messenger RNA (mRNA) to code for Cas13, an enzyme that is known to target RNA viruses. In hamsters, delivery of this Cas13a mRNA through a nebuliser reduced SARS-CoV-2 replication and reduced symptoms.
More on vaccines
A further analysis of the trials for the Oxford /AZ vaccine provides some additional information: there were no hospitalisations in the vaccine group after the initial 21-day exclusion period, as compared to 15 in the control group; vaccine efficacy after one dose of vaccine from day 22 to day 90 post vaccination was 76%; and, in the group that received two full doses, efficacy was higher with a longer interval between doses: 82% for a 12 week interval versus 55% for an interval of 6 weeks or less. PCRs made on swab samples obtained from vaccinated individuals also suggest the vaccine could help reduce viral transmission.
Many countries saw cancer diagnostics and treatment partially or completely disrupted during the pandemic (in Spain, for example, the number of cancer diagnosis fell by 20% in 2020). This means that cancer’s death toll will surely increase in the coming years.
[Evidence published between 27/01/2021 and 02/02/2021]
One year ago (Jan 30, 2019), the WHO declared the outbreak of COVID-19 a Public Health Emergency of International Concern, with around 8,500 confirmed cases globally. Today we stand at 103 million cases.
A study in South Korea confirms that, in average, infected people are no longer contagious 7 days after symptom onset, even if they can remain positive by PCR for more than 30 days. The study performed viral culture and PCRs from patients hospitalized with COVID-19.
Another risk factor
Schizophrenia may be a risk factor for mortality in patients with COVID-19, according to a retrospective cohort study with 7348 adult patients in New York.
A broad diversity of T cells
Patient-derived T cells recognise a broad range of SARS-CoV-2 protein fragments (or epitopes) – at least 30 to 4o epitopes in each donor. These T cell epitopes hardly overlap with epitopes recognised by antibodies, making it less likely that the new variants can also escape T cell immunity.
Worrying signs from Manaus
In Manaus, Brazil, a study of blood donors indicated that around 76% of the population had been infected with SARS-CoV-2 by October, 2020, which would be above the theoretical herd immunity threshold. However, there has been an abrupt increase in COVID-19 hospitalisations during January 2021. Possible explanations include the higher transmissibility of the P1 variant and/or its potential capacity to escape from immunity.
Only one dose for some people?
Results from two studies (not yet peer-reviewed) suggest that, in people who have already been infected by SARS-CoV-2, one single vaccine dose (Pfizer or Moderna) induces antibody titers equal to or higher than those found in “naïve” (non-infected) individuals after two doses.
Efficacy data for two more vaccine candidates
Novavax announced its protein-based vaccine showed an 89.3% efficacy in its trial in the UK, with over 15,000 participants between 18 and 84 years of age. Of 62 symptomatic cases, 56 (1 of them severe) were in the placebo and 6 in the vaccine group. Over 50% of cases were infected with the B1.1.7 variant, indicating that the vaccine also works against this variant. However, the efficacy dropped to 60% in a smaller trial (4,400 participants) in South Africa, where the B1.3.5 variant is circulating. The efficacy was lower (49.3%) when including HIV-positive people.
Johnson & Johnson also announced efficacy data for its adenoviral-vectored vaccine. One single dose protected from symptoms although efficacy depended on the location: from 72% in the US to 66% in Mexico and 57% in South Africa. Importantly, the trial had enough cases to conclude that, by 28 days after the shot, the vaccine provided an 85% protection against severe cases and complete protection against hospitalisation and death, even in South Africa.
The Gamaleya Institute published the interim results for the phase 3 trial of its vaccine candidate (Sputnik V), based on two adenoviral vectors. The results show the vaccine was safe and had an efficacy of 91.6%, even in people older than 60.
Companies are already planning how to update their vaccines against the new variants, if necessary.
The European Medicines Agency has approved the use of AstraZeneca’s vaccine for people from 18 years of age. Although there are not enough efficacy data in participants over 55, the EMA considered the vaccine can be used in this population.
COVAX starts to deliver
The COVAX platform expects to deliver 35.3m doses of AstraZeneca’s COVID-19 vaccine to 36 Caribbean and Latin American countries from mid-February to the end of June, PAHO announced.
[Evidence published between 20/01/2021 and 26/01/2021]
More on viral variants
Moderna has announced that its vaccine retains neutralising activity against the variants first identified in the UK (B1.1.7) and South Africa (B1.351). Although a six-fold reduction in virus neutralisation was observed with the B1.351 variant, the titers of neutralising antibodies after two doses of the vaccine remain above those needed for protection. The company is nevertheless preparing a shot against this variant, in case it becomes necessary.
Not so good news?
According to a report by an advisory group in the UK, new analyses show there may be an increase in disease severity in patients infected with the B1.1.7 variant. However, more data are needed to draw firm conclusions.
The virtues of contact tracing
An analysis of COVID-19 fatality rates in 139 countries shows, quite unsurprisingly, that comprehensive contact tracing is instrumental not only for slowing transmission but also for reducing cases fatality rates.
Estimating asymptomatic infections
Data collected from numerous studies and reports indicate that at least one third of total SARS-CoV-2 infections are truly asymptomatic (i.e. they never develop symptoms).
“Bad” kind of antibodies
Increasing evidence suggests that antibodies directed against our own proteins or tissues (called autoantibodies) could be driving severe disease upon SARS-CoV-2 infection. Autoantibodies recognising a variety of targets - including interferon, B cells and other components of the immune system as well as components of the cell membrane such as phospholipids and more recently Annexin A2 - have been detected in patients with severe COVID-19. This could explain the long-lasting damage to certain organs observed in some of these patients.
More on treatments
A series of large clinical trials conducted worldwide show that treatment of moderately ill patients with a full dose of heparin (an anticoagulant) reduced the need for ventilation.
A combination of two monoclonal antibodies developed by Eli Lilly significantly lowered viral loads in mild to moderately ill patients by day 11, as compared to those who received placebo.
In addition, the company announced that one of those antibodies (bamlanivimab) reduced the risk of developing COVID-19 symptoms by up to 80% among nursing home residents treated preventively with the drug. Although the antibody does not substitute the vaccine, it could be used to prevent outbreaks when it is too late to vaccinate.
Another study engineered a human monoclonal antibody that can recognise and neutralise a broad range of SARS-like viruses.
A drug from the sea
Plitidepsin, an anticancer drug derived from a marine invertebrate, was shown to be much more potent than remdesivir against SARS-CoV-2 in cell lines and reduce viral replication in mice infected with the virus. The drug, developed by the Pharmamar company under the name of aplidin, now needs to be tested in patients with COVID-19.
More on vaccines
Preclinical studies with mice and/or baboons show promising results for Novavax’s vaccine candidate (comprising nanopoarticles of the Spike protein) and for a vaccinia virus-based candidate (MVA-CoV2-S) developed by a Spanish team.
In contrast, Merck announced it will stop developing its both vaccine candidates, following phase 1 results which showed that, although well tolerated, the immune response to the shot was lower than that observed upon natural infection.
Out of 1.9 million doses of the Pfizer vaccine administered in the US between December 14 and 30, 2020, 21 cases of anaphylaxis were reported, corresponding to an estimated rate of 11 cases per million doses administered. No deaths were reported.
In Israel, 75% of the older population has been vaccinated and this is starting to show: there has been a 60% drop in hospitalisations among vaccinated older people, according to recent data. Assessing the impact of vaccination on transmission at the population level will need more time.
For the world’s top billionaires, it only took nine months to recover their pre-pandemic fortune. For the world’s poorest, it may take more than a decade, according to Oxfam’s report The Inequality Virus. The pandemic has the potential to increase economic inequality in almost every country at once - the first time this happens since records began.
[Evidence published between 13/01/2021 and 19/01/2021]
A precursor of the B1.1.7 variant?
Genome sequencing of virus isolated from an Italian patient with persistent infection suggests that SARS-CoV-2 variants with a mutation at position 501 of the Spike protein might have circulated even before September 2020. The virus evolved within the same patient, accumulating three additional mutations in less than three months.
Experts agree that, when analysing the possible effect of SARS-CoV-2 mutations in this and other variants, it is important to look beyond one single point mutation and consider the interactions between the different mutations. This involves integrating genomic data with clinical evidence and laboratory studies.
SARS-CoV-2 can infect the brain
SARS-CoV-2 can infect neurons in the brain cortex and alter their metabolism, according to a study that used three independent approaches to confirm this: human brain organoids in a dish, mice expressing the human ACE2 receptor, and autopsies from deceased COVID-19 patients.
Impact of the COVID-19 pandemic in Brazil
A study of the first 250,000 patients hospitalised with COVID-19 in Brazil shows that almost half were under 60 years-old and two of every five patients died. In-hospital mortality was higher in areas with fragile health systems.
More good news regarding duration of immunity
Memory B cells to SARS-CoV-2 persist for more than 6 months and produce antibodies that are more potent and likely more resistant to mutations in the Spike protein than those produced one month after infection, according to a study by the Rockefeller University.
A UK study that followed 20,000 healthcare workers shows that people that have had COVID-19 are likely to be protected from disease for several months, although some may still become infected in nose and throat and transmit the virus.
From pandemic to endemic
A model predicts that, once SARS-CoV-2 becomes endemic, exposure during early childhood will cause no more than a common cold but will be enough to induce long-lasting immunity that protects from severe disease later in life.
Results for more vaccine candidates
Phase 1/2 results for another viral vector vaccine candidate
The safety and immunogenicity results for Janssen’s Ad26-based COVID-19 vaccine candidate show that neutralizing antibodies were detected in all participants between 30 and 60 days after one single shot. Antibody and T cell responses were lower in adults aged over 65 years, raising the question whether one single shot will be enough to protect this population. In fact, those participants who received a second dose showed a further increase in antibody levels. A phase 3 trial with one versus two doses of the vaccine is currently underway.
Final efficacy results for Sinovac’s vaccine?
Brazilian researchers announced the efficacy of Sinovac’s inactivated virus vaccine was around 50% (after having announced an efficacy of 78% last week). Of the 9200 health workers who participated in the trial, 167 cases were recorded in the placebo group and 85 in the vaccinated group. None of the vaccinated cases had to be hospitalized. A Sinovac spokesman said that the vaccine efficacy was higher (around 70%) if the dosing interval was longer (three weeks instead of two). Turkey and Indonesia, who also performed clinical trials with the vaccine, have authorised its use.
Vaccination: a very unequal start
Over 39 million vaccine doses have been administered in 49 high-income countries. Only 25 doses have been given in one low-income country. “The world is on the brink of a catastrophic moral failure”, said WHO’s director, Dr. Tedros Ghebreyesus.
[Evidence published between 06/01/2021 and 12/01/2021]
One year ago, the first death from COVID-19 was reported. Today, the world has reached almost 2 million deaths.
More on viral variants
An updated analysis by Public Health England indicates that 15% of the contacts of people infected with the B.1.1.7 variant went on to test positive themselves, compared with 11% of contacts of those infected with other variants. Increased transmission is observed across all age groups, arguing against a special effect in children.
Preliminary experimental data suggest that the mutations of the B1.1.7 lineage do not affect recognition by antibodies resulting from natural immunity or from immunisation with the Pfizer vaccine. However, the E484 mutation – present on a strain that is rapidly spreading in South Africa and another one in Brazil – could potentially reduce the effect of neutralising antibodies, according to another study.
Estimating the percentage of infected people
A study using data of reported cases and seroprevalence surveys estimates that by mid-November 14,3% of the population in the US had been infected with SARS-CoV-2. This is 3 times higher the number of reported cases at the time but still far from reaching herd immunity.
According to recent estimates based on the number of COVID-19 deaths and the infection fatality rate, one in five people (22%) in England may have been infected.
And two studies in Africa suggest that the virus may be more widespread than thought: Analysis of antibodies among blood donors in Kenya shows an average seroprevalence of 4.3%, while another study with over 700 health volunteers in the Congo shows that 15% had antibodies against the virus.
A follow-up study in China with over 1,700 COVID-19 patients shows that 6 months after the onset of symptoms, around 75% of survivors still had at least one symptom (mostly fatigue, muscle weakness, sleep difficulties and anxiety or depression). A considerable percentage of those who were severely ill still had abnormal lung function, underlining the need of providing post-recovery care for these patients.
On the importance of IgA antibodies
Two studies this week underline the role of IgA antibodies in viral clearance. One study shows that IgG, IgM and IgA antibodies are produced early in the disease, but that IgAs may be better at neutralising virus and controlling the infection. IgA antibodies decreased in blood after one month, but remained detectable in saliva up to 73 days after symptoms. Another study shows that dimers of IgA (which are the dominant form in the nasal and throat mucosae) are much more potent in neutralising SARS-CoV-2 than monomers (which are found in blood).
Immune memory: at least 8 months
Science has published the results of a study that analysed the different compartments of immune memory to SARS-CoV-2. IgG antibodies to Spike were relatively stable over more than 6 months, Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptoms, and the estimated half-life of virus-specific T cells was of 3-5 months.
More solid results for two treatments
Convalescent plasma: yes, if given early?
A controlled clinical trial in Argentina showed that convalescent plasma can reduce COVID-19 progression in older adult patients if given within the first 72 hours after the onset of symptoms and if the plasma is screened for high titers of SARS-CoV-2 antibodies.
A trial in the UK shows that in critically ill COVID-19 patients, treatment with the IL6 antagonists tocilizumab and sarilumab (normally used for rheumatoid arthritis) can improve disease outcome and increase survival. The results have not yet been peer-reviewed.
More on vaccines
Indonesia has approved the inactivated virus vaccine developed by the Chinese company Sinovac, after an interim analysis of phase 3 results showed an efficacy of 65%. The same vaccine was reported to have a 78% efficacy in Brazil. Detailed data for these vaccine trials have not yet been published.
Gorillas get it too
Several gorillas at San Diego Zoo have tested positive for SARS-CoV-2 and are showing some mild symptoms. Wildlife experts are concerned about the virus infecting gorillas and other endangered apes.
[Evidence published between 23/12/2020 and 05/01/2021]
More on viral variants
A report published by the Imperial College, based on genetic and epidemiological data, indicates that a larger share of people under 20 are being infected with the UK variant (named B1.1.7). For now, all data indicate that this variant is indeed more transmissible. Although the precise reasons are still not known, B1.1.7 presents three mutations in the spike protein that may have biological effects:
- Mutation N501Y is within the domain that binds to the ACE2 receptor, and may increase the affinity with which the virus binds to such receptor. This mutation has been identified in a South African variant (named 501.V2), which also seems to be spreading faster.
- A deletion of two amino acids (69,70 del) may help evade the effect of certain antibodies. This deletion was also described in a variant isolated from a mink farm in Denmark.
- Mutation P681H is next to a site (called furin cleavage site) that enhances viral infectivity. This same mutation has been found in a separate variant identified in Nigeria.
One hypothesis is that this variant may have risen in an immunocompromised patient, where a weakened immune system gives an opportunity for the virus to evolve. In fact, a study shows that patients with profound immunosuppression may remain infected with SARS-CoV-2 for at least two months.
Modelling estimates suggest that, with the new variant, reducing the Rt to less than 1 will require stricter lockdown measures.
The emergence of this and other potentially worrying variants further underlines the urgent need to curb viral spread and vaccinate as rapidly as possible.
Need for more efficient testing
An analysis in France found that 9 out of 10 cases were not detected in the first seven weeks following lockdown from May 11 to June 28 2020, even if the test positivity rate did not exceed WHO recommendations (5%). Only 31% of individuals with COVID-19-like symptoms consulted a doctor in the study period. More aggressive and targeted testing with easier access is required to fight the pandemic.
Further data on antibody duration
A follow-up study of 12,541 health care workers in UK shows that the presence of IgG antibodies against the spike or nucleocapsid proteins of SARS-CoV-2 was associated with a substantially reduced risk of SARS-CoV-2 infection in the following 6 months. Only two seropositive individuals had a positive PCR test during the 31 weeks of follow-up, and both infections were asymptomatic.
Along the same line, a South Korean study detected virus-specific antibodies up to 8 months after asymptomatic or mild infection with SARS-CoV-2 by using four different tests.
More vaccines approved
The UK approved AstraZeneca-Oxford’s vaccine on December 30 and has started to roll out the vaccine, of which it has ordered 100M doses. The UK plans to stretch the interval between the two doses required to allow more people to get the first dose sooner. However, experts have raised concerns that this could favour the generation of vaccine-resistant strains by building a cohort of partially immunised individuals. The European Medicine Agency has advised against spacing the two shots of the Pfizer vaccine more than 42 days.
India has formally approved the emergency use of 2 COVID vaccines: The one developed by AstraZeneca /Oxford University (known as Covishield and produced locally by the Serum Institute of India), and one based on inactivated virus developed by Bharat Biotech (named Covaxin), for which no efficacy data have been published.
[Evidence published between 16/12/2020 and 22/12/2020]
A new viral variant - reason for concern but not for panic
A new variant that has rapidly spread in the UK (named B1.1.7) has accumulated 17 mutations all at once, of which 9 are in the Spike protein. The impact of these combined mutations is still not clear, but three questions arise:
Is it more transmissible?
Probably. Preliminary analyses suggest that this new variant may be up to 70% more transmissible than other circulating variants. This observation is supported by experimental data, which show that one of the mutations (N501Y) may increase viral binding to the human ACE2 receptor. This mutation is also present on a separate lineage in South Africa that has been rapidly spreading.
Is it more virulent?
No evidence for the moment. One of the mutations (involving the deletion of two amino acids) has been observed in other lineages, and one study suggests it could make the virus less susceptible to neutralising antibodies. However, at this time there is no evidence that the variant causes more severe disease.
Can it escape from natural or vaccine-induced immunity?
Unlikely, experts say. Even if one fragment of Spike changes, antibodies and T cells can recognise many different fragments of the protein.
Meanwhile, the ECDC has given a series of recommendations, which include reinforcing measures to stop viral spread and increasing the analysis and sequencing of virus isolates, particularly in people coming from affected areas, in suspected cases of reinfection, and in vaccinated individuals who develop the disease.
Transmission by asymptomatic individuals
A study in Singapore suggests that people with asymptomatic SARS-CoV-2 infection might be less infectious than symptomatic cases: the incidence of COVID-19 among close contacts of a symptomatic index case was 3·85 times higher than for close contacts of an asymptomatic case.
At least 10% of the Spanish population (over 4.5M people) has been exposed to SARS-CoV-2, according to results from the fourth phase of the national seroprevalence study (ENE-COVID). Seroprevalence was highest in healthcare workers (17%), women carers (16.3%), women cleaners (13.9%), women in socio-sanitary jobs (13.1%) and migrants (13%).
Another seroprevalence study in Geneva shows that 22% of its residents has virus-specific antibodies. The study shows a higher than expected prevalence of infection among children over 6 (23%). The less exposed were children under 6 (15%) and adults over 65 (10-14%). The most exposed were those aged 18 to 35 (27-28%).
Leading cause of mortality in the US
By October, COVID-19 became the third cause of death in the USA for persons aged 45 and older. Between November and December, it has become the first cause of death, surpassing daily mortality rates for heart disease and cancer. The USA, which constitutes 4% of the globe's population, has contributed to 19% of the global total of deaths (as of 14 Dec 2020).
More on vaccines
Codagenix and the Serum Institute of India announced they will start Phase 1 trials for COVI-VAC, an intranasal vaccine based on live attenuated virus developed using synthetic biology. The trial will be conducted in London.
The US FDA has granted emergency use authorisation to Moderna’s vaccine for use in adults aged 18 or older. Vaccine efficacy was 94.1% - 11 COVID-19 cases in the vaccine group and 185 cases in the placebo group. All severe cases (30) occurred in the placebo group.
And the European Medicines Agency (EMA) authorised Pfizer/BioNTech’s vaccine for use in the bloc’s 27 states. The EU has ordered 300 M doses but only a limited number will be available immediately.
[Evidence published between 10/12/2020 and 15/12/2020]
Evidence of early circulation?
An Italian team found SARS-CoV-2 RNA in a throat swab collected from a child in early December 2019, around 3 months before the first identified coronavirus disease case in Italy. The child had not travelled, so this finding raises the possibility that the virus was circulating outside China earlier than thought.
Impact on male fertility?
A small study on testis biopsies from COVID-19 patients reveals the virus can infect germ cells and affect the production of spermatozoids. These findings raise the possibility that the virus may affect male fertility.
A mortality risk calculator
A Johns Hopkins University team generated an online risk calculator for COVID-19 mortality based on sociodemographic factors and pre-existing health conditions for the US population. The model can identify relatively small fractions of the population that might experience a disproportionately large number of deaths, and could help set priorities for allocating early COVID-19 vaccines.
In the period between March and July, UK health care workers had a seven-fold higher risk of becoming severely sick from COVID-19 than non-essential workers, and this risk was even higher (8-fold) if they were non-white. Social and education workers were also at higher risk (1-8-fold) as compared to non-essential workers, according to the analysis.
More on treatment
No benefit for an antibiotic
The UK RECOVERY trial found no benefit from azithromycin in patients hospitalised with COVID-19. The preliminary analysis shows no significant difference in mortality, disease progression or length of hospital stay between treated and control groups.
More on vaccines
The final Phase 3 results for the Pfizer-BioNTech vaccine were published this week. The two doses, given 21 days apart, were safe and 95% effective against COVID-19. Similar vaccine efficacy was observed in groups of different age, sex, ethnicity, body mass index or underlying health conditions. Ten cases of severe COVID-19 occurred after the first dose, 9 of them in placebo recipients and one in a vaccine recipient. Short-term side effects including pain at the injection site, fatigue, and headache were frequent. The incidence of serious adverse events was very low and similar in both groups. Safety monitoring of participants will continue for 2 years.
A trial may start soon to find out whether mixing COVID vaccines gives better protection than 2 doses of the same one. AstraZeneca will test combining one shot of its vaccine with a second shot of Pfizer’s vaccine. This heterologous prime-boost approach seeks to induce stronger cellular and humoral responses than with one single type of vaccine. It will also explore combining its vaccine with Gamaleya’s Sputnik V vaccine (which uses different adenoviral vectors).
Bad news for two vaccine candidates
Sanofi has suffered a setback in the development of their recombinant protein-based vaccine it is developing with GSK, after detecting a lower response in older adults due to a dosing problem in their formulation. This means that, if approved, it will not be deployed before the second-half of 2021.
The University of Queensland has decided to end the development of its recombinant protein vaccine after finding that vaccinated volunteers developed antibodies that could give false HIV-positive results. This is because the vaccine included a small “molecular clamp”, derived from a protein of HIV, to stabilise the SARS-CoV-2 Spike protein.
[Evidence published between 2/12/2020 and 9/12/2020]
Rapid nucleic tests without amplification
Two studies have described rapid tests capable of detecting SARS-CoV-2 ARN without having to amplify it. One test uses DNA probes that bind to specific regions in the viral genome, followed by fluorescent antibodies that detect these DNA-RNA hybrids. The assay achieved sensitivities of 100% and specificities of 99% for both saliva and nasopharyngeal swabs and gives results in less than one hour. The other test uses the CRISPR-Cas13a system to directly detect SARS-CoV-2 RNA in nasal swabs. Binding of Cas13a to specific viral sequences leads to the activation of fluorescent DNA probes. The results can be read in 30 minutes using a mobile phone reader device.
More on the dynamics of transmission
A global analysis to understand where SARS-CoV-2 transmission takes place, shows that the highest transmission rates are seen in households (a 21.1% probability of infection). The report from the Imperial College London also reveals that the chance of a symptomatic infected person infecting a close contact was 12.8%, which was four-times higher than if he or she was asymptomatic (3.5%).
Another study (not yet peer-reviewed) that performed regular PCRs on 68 basketball players shows that, on average, viral RNA concentrations peaked rapidly after the first detection (within 2.7 days), regardless of symptoms. However, asymptomatic individuals cleared the virus more rapidly (6.7 days) than symptomatic individuals (10.5 days). These studies raise hopes that, by reducing symptomatic infections, vaccines may also help reduce viral transmission.
A German study concludes that 20 days after becoming mandatory, face masks reduced the number of new infections by around 45%.
"Untuned" immune responses
Normally, type I and III interferons (IFN) are produced as a first line of antiviral defence, and precede the production of inflammatory cytokines. However, in COVID-19 patients with pneumonia, the production of pro-inflammatory cytokines (TNF, IL6, IL8) was shown to precede that of IFN type I and III, which were diminished and delayed.
Another potential treatment
A ribonucleoside analogue (which disrupts viral RNA) was repurposed for use against SARS-CoV-2. Therapeutic treatment of infected ferrets twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. The drug, which can be given orally, is currently in Phase 2/3 clinical trials.
Ethical issues regarding vaccine trials
Now that some vaccines have shown to be effective, one question starts to emerge: should the vaccine be offered to the volunteers who got a placebo shot at the risk of losing valuable long-term information? This week, two groups of experts defend the need to continue having placebo-controlled trials. As long as vaccine supplies are limited, one group argues, it is ethical to continue the follow-up of placebo recipients in existing trials and to launch new trials with placebo groups. This would increase the probability of developing multiple vaccines with favourable benefit /risk profiles. The other group says that any plans to conduct placebo-controlled trials remain ethically appropriate given current evidence, and proposes to guarantee that individuals in the placebo arm will receive an efficacious vaccine once their participation in the study is completed. An article in the New York Times includes an interesting proposal: after several months, continue the blinded study giving placebo to the vaccine group and vaccine to the placebo group, and compare duration of immunity between both groups.