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 06/01/2020 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.
[Evidence published between 25/11/2020 and 1/12/2020]
Mutations under the magnifying glass
A phylogenetic analysis of more than 47,000 SARS-CoV-2 genomes isolated from patients worldwide finds no evidence for recurrent mutations associated with increased viral transmission. Mutations identified so far seem to be evolutionary neutral rather than a result of viral adaptation.
Shorter isolation periods?
People are most infectious between two days before and five days after symptoms begin, according to an analysis that reviewed published data. This raises the possibility of considering shortening the recommended isolation period (which is currently of 10 days in many countries). France has already dropped it to seven days, and Germany is considering shortening it to five days.
The value of saliva
A pilot study (not yet peer-reviewed) led by Hospital Sant Joan de Deu, Barcelona, shows that direct PCR on saliva is a simple, rapid, and accurate method for screening for SARS-CoV-2. Saliva is easier to collect and the risk of aerosols is reduced.
Understanding the loss of smell
Cells that provide support to our olfactory neurons express receptors that allow SARS-CoV-2, providing the virus with a potential ‘entry door’ into the brain, according to a study that analysed gene expression in the olfactory system. Accordingly, another study (not yet peer-reviewed) reveals viral presence in olfactory mucosa of COVID-19 patients who lost their sense of smell.
Controversy regarding cross-reactive T cells
An analysis of T cells recognising common cold coronaviruses and SARS-CoV-2 finds that T cells in patients with severe COVID-19 have a low avidity (i.e. they do not bind strongly to viral peptides). Contrary to what other studies suggest, the findings also suggest that T cells reactive with common cold coronaviruses do not protect against COVID-19.
More on treatment
A controlled clinical trial of convalescent plasma for the treatment of COVID-19 severe pneumonia showed no benefit in terms of clinical outcomes or mortality, despite the fact that levels of IgG antibodies to SARS-CoV-2 were controlled before transfusion.
More vaccine efficacy data
Moderna announced final phase 3 results for its mRNA vaccine candidate, showing 94% efficacy (a total of 196 cases of symptomatic COVID-19 in the 30,000-volunteer study, with 185 cases in the placebo group and 11 in the vaccine group). There were 30 cases of severe Covid-19 and 1 death in the placebo group, and none in the vaccine group. The company is now applying for approval to the US FDA and the European Medicines Agency.
Meanwhile, the Sputnik V vaccine developed by Gamaleya Institute has reported an efficacy of 91.4%, based on a second interim analysis with 39 cases among almost 19,000 participants: 8 in the vaccinated group and 31 in the control group. The vaccine uses two different adenoviral vectors expressing the viral Spike protein: a first shot with Ad26 followed 21 days later by a second shot with Ad5.
[Evidence published between 18/11/2020 and 24/11/2020]
Rapid testing for detecting infectious people
A modelling study shows that frequent testing and rapid results may be more important than high test sensitivity for the effective screening of populations.
Along this line, the University of Oxford showed that some of the rapid tests that are being evaluated can miss some infected people but can detect those most infectious: one test detected 77% of all PCR-positive individuals but over 95% of individuals with high viral loads.
Other, more sensitive, rapid tests are also being developed: the US FDA has approved the first molecular diagnostic test that can provide results in 30 minutes and can be used as a self-test at home.
More evidence for long-lasting immunity
One of the largest follow-up studies to date, performed with 12,219 healthcare workers in the UK, shows that antibody responses generated after a first SARS-CoV-2 infection offered protection from reinfection for most people during at least six months. This study has not yet been peer-reviewed.
Another survey in a large cohort of children between 2 and 15 years of age, shows that antibody titres in children exposed to SARS-CoV-2 remain at a detectable level for at least 62 days, with some antibody titres increasing over time. This is consistent with recent findings in adults.
Indeed, a study (not yet-peer reviewed) suggests immunity to SARS-CoV-2 may last several months, or even years. The researchers analysed multiple arms of immune memory to SARS-CoV-2 in almost 200 COVID-19 cases, and found that IgG antibody levels were relatively stable over six months, and that virus-specific memory B cells (which produce antibodies) were more abundant at 6 months than at 1 month. Virus-specific T cells decayed slowly, with a half-life of 3-5 months. Another study found very similar results, even in patients with mild COVID-19.
More on treatment with monoclonal antibodies
Pairs of antibodies may be more effective than single antibodies at preventing and treating COVID-19, according to a study that tested different human monoclonal antibodies in animal models of SARS-CoV-2 infection. The results also show that some antibodies may prove more potent in vivo (inside the body) than in vitro (in a lab dish).
One antibody combination, developed by Regeneron, has been approved by the US FDA for the treatment of mild to moderate COVID-19 in adults and children 12 years of age or older.
Antibodies in breast milk
Milk from COVID-19 recovered mothers contains antibodies that can neutralize the virus (specially IgA antibodies) and that could protect the babies from infection, according to a study.
Vaccines: three steps closer
AstraZeneca announced interim results for its vaccine AZD1222, developed with Oxford University, based on 131 infections (30 0f them in the vaccine group and 101 in the control group). Efficacy was of 62% in people who received two full doses, one month apart, and up to 90% in a smaller group that received half a dose, followed by one full dose (the reasons for this difference are not yet known). The advantage of this vaccine, as compared to that of Pfizer or Moderna, is that it can be kept in a normal refrigerator, for up to six months, which would facilitate its distribution in rural settings and low-income countries.
Although it is too early to know whether the AstraZeneca vaccine is equally effective in elderly people, phase 2 trial results published this week show that it was better tolerated in older adults and as immunogenic as in younger adults.
Sinovac also published phase 1 /2 results for its inactivated virus vaccine candidate (CoronaVac) candidate. The low dose was safe and well-tolerated, and neutralising antibodies were induced, albeit at lower levels than those observed in convalescent patients. The vaccine is currently being tested in phase 3 trials, with thousands of volunteers.
The WHO has warned again of the risk that the poorest and most vulnerable populations will not have access to the vaccines, and insisted on the urgency to distribute them fairly.
[Evidence published between 12/11/2020 and 17/11/2020]
This week, the world reached its highest daily death toll by COVID-19, since the pandemic began.
Two receptors are better than one
SARS-CoV-2 can infect human cells thanks to the binding of its Spike protein to the human ACE2 receptor on the cell surface. Two studies published in Science show that a segment of the viral Spike protein can also bind to another protein on the surface of human cells (called neuropilin 1), greatly enhancing the infective capacity of the virus. These results suggest that the interaction between Spike and neuropilin 1 can be another potential therapeutic target.
Pinning superspreader events
Using data from cell phones data and mobility networks, researchers mapped the hour by hour movements of 98 million people. Their model predicts that a small minority of “superspreader” places (mainly restaurants, gyms, cafes, houses of worship) account for a large majority of infections, and that limiting occupancy in these places is more effective than general lockdowns.
A close look at T cell immunity
A study looking at immune responses in COVID-19 patients suggests that virus-specific CD8+T cells play a key protective role. Virus-specific CD8+ T cells were detectable even in convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting viral proteins Spike and nucleoprotein.
Repurposing existing drugs
Inhaling interferon beta
Patients who received an inhaled form of interferon beta-1a, one of the first molecules induced upon viral infection, recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, according to a phase 2 clinical trial involving adults admitted to hospital with COVID-19.
More on ACE2 traps
Another team of researchers has developed soluble human ACE2 receptors that act as “decoys”, neutralising the virus before it binds to and infects human cells. These decoy receptors protected hamsters from viral infection.
A drug for rheumatoid arthritis
Artificial intelligence analyses have identified baricitinib, an immunosuppressor used for rheumatoid arthritis, as a potential drug for COVID-19. In a small trial in hospitalised COVID-19 patients, the drug reduced inflammation, progression to severe disease, and mortality.
Two steps closer to a vaccine
Moderna has announced early results for its mRNA vaccine candidate, which appears to have an efficacy of 94.5%. The analysis was based on 95 cases of COVID-19, of which 90 cases were observed in the placebo group and 5 cases were observed in the vaccine group. In addition, all severe cases occurred in the placebo group. In contrast to the Pfizer mRNA vaccine, the Moderna vaccine can be kept at refrigerator temperatures for one month. The technology used by both vaccines had never before been approved for use in humans, but these results suggest it can be used for the rapid design of vaccines for other pathogens.
But not for all
Wealthy nations, representing only 13% of the world’s population, have already reserved more than half (51%) of the doses promised by leading COVID-19 vaccine candidate manufacturers, says an Oxfam report. This means that most of the world’s population may not be vaccinated before 2022.
[Evidence published between 4/11/2020 and 10/11/2020]
Symptoms and risk factors
Severe lung damage
An analysis of lungs from individuals who died of COVID-19 reveals extensive lung damage and blood clots, as well as a large number of abnormal, fused cells that remain infected and which could eventually explain long COVID.
Pregnancy increases the risk of severe complications and death, according to an analysis of approximately 400,000 women aged 15–44 years with COVID-19.
More on immunity
Shorter duration of COVID-19 symptoms was associated with sustained antibody production, higher frequencies of activated T cells, and increased mutations in antibody genes (which allows them to bind better to the virus), according to a study that followed symptomatic subjects for over 100 days.
Individuals who have not been exposed to SARS-CoV-2 (particularly children and adolescents) may have cross-reactive IgG antibodies that recognise the S2 domain of the viral Spike protein, which is relatively conserved between different coronaviruses. In contrast, antibodies that recognise the S1 domain are only found in individuals that have been infected by SARS-CoV-2, a study shows.
Virus-specific treatments in the pipeline
The SARS-CoV-2 virus needs to binds to the ACE2 receptor on human cells, in order to infect them. A team has designed soluble ACE2 receptors that act as “traps” and neutralize the virus as effectively as antibodies isolated from convalescent patients. They also bind viral spike proteins from other coronaviruses known to cause respiratory diseases.
Two studies in Science describe extremely potent neutralizing nanobodies (i.e. single-chain antibodies that are smaller and easier to produce) that could be used as treatment: a cocktail of llama-derived nanobodies that bind to different regions of the receptor binding domain of the viral Spike protein, and a synthetic, trivalent nanobody with an extremely high affinity for Spike. These nanobodies can be rapidly produced, lyophilised and delivered intranasally as a spray.
Vaccines: one step closer
Pfizer/BioNTech announced that an early interim analysis suggests their mRNA vaccine was strongly effective – 90% fewer cases were observed among individuals who received two doses three weeks apart, as compared to placebo. Volunteers must be followed-up for at least two months to survey safety issues before the company can apply for an emergency use authorization. For the moment, it is not clear whether the vaccine prevents disease or infection and which age groups are protected. The downside of mRNA vaccines is that they require storage at very low temperatures, which complicates their distribution.
Overall, these are good news for the other vaccine candidates, which also use the viral Spike protein as immunogen, CEPI points out.
Tiny artificial ball-shaped particles displaying many copies of the viral Spike protein in different conformations induced potent and protective antibody responses against SARS-CoV-2 in mice. These nanoparticle vaccines are stable and can be produced at large scale, and will start to be tested in humans.
A prophylactic nasal spray?
A team from Columbia University has released preliminary results (not yet peer-reviewed) showing that intranasal administration of a lipopeptide that binds to the virus Spike protein completely prevents SARS-CoV-2 infection in ferrets. These lipopeptides are inexpensive, highly stable and non-toxic. If they work in humans, they could be used as a prophylactic to prevent infection by SARS-CoV-2.
Mink and viral variants
Denmark announced it will cull its entire herd of 17 million mink, after detecting a unique viral variant in five mink farms and 12 human cases. According to Danish authorities, laboratory experiments suggest this variant is slightly less susceptible to antibodies in convalescent plasma, which could have implications for future vaccines. There is no evidence for the moment that this variant is more dangerous or transmissible, and the findings need to be confirmed and further evaluated.
[Evidence published between 28/10/2020 and 3/11/2020]
Blocking viral egress?
A study shows that beta coronaviruses (including SARS-CoV-2) use another pathway to egress infected cells as compared to other enveloped viruses. This unconventional pathway, which involves organelles called lysosomes, represents a therapeutic target.
A European variant
A new SARS-CoV-2 variant called 20A.EU1 emerged this summer in Spain and spread to other European countries. For the moment, there is no evidence that the rapid spread of this variant is due to particular properties of the virus.
Long-term exposure to air pollution could be linked to 15% of global deaths from COVID-19, according to a study. Researchers estimated global exposure to fine particulates based on satellite data and associated it with epidemiological data.
More on antibodies and immunity
An analysis with 30,ooo individuals shows that the vast majority of infected individuals with mild-to-moderate COVID-19 develop robust IgG antibody responses against the viral spike protein. Furthermore, titers were relatively stable for at least 5 months and correlated with capacity to neutralise the virus.
A dual assay that measures antibodies to two SARS-CoV-2 proteins reveals a 6-fold higher antibody prevalence in children than previously reported (0.9% instead of 0.15%). The study was performed in 15,771 children (aged 1-18) living in Bavaria, Germany.
Monoclonal antibodies- only if given early
Interim results for Eli Lilly’s monoclonal antibody LY-CoV555 in non-hospitalised patients show a modest effect on viral load and a slight reduction in the % of patients who visited the hospital or emergency services (1.6% versus 6.3% in placebo group).
REGENERON also announced positive results from an ongoing trial among non-hospitalised patients. Its antibody cocktail significantly reduced viral load and patient medical visits by 57%
In contrast, both companies stopped their antibody trials with hospitalised, severe COVID-19 patients after interim results showed no benefit for these patients. This is not surprising, since these antibodies are expected to inhibit viral replication early on, but not the inflammation associated with severe disease.
More vaccine candidates
Three new candidates have entered phase 1 trials, including Canada’s Symvivo vaccine, based on engineered bacteria packaged into a pill, which synthetise viral Spike protein when they reach the intestine.
[Evidence published between 21/10/2020 and 27/10/2020]
A more transmissible viral variant?
A viral variant with a mutation in the spike protein became dominant early in the pandemic. A study shows that hamsters infected with this variant (called D614G) have higher viral loads in the nose and trachea, suggesting that it may be more transmissible. However, the study also concludes that this mutation should not affect the efficacy of the vaccines currently tested.
Universal mask use in the US could save 130,000 lives between September 2020 and February 2021, according to a modelling study.
A study from King’s College, London, estimates that one in 20 people with COVID-19 are sick for at least eight weeks. Old age, being female, and having more than five different symptoms in the first week, were identified as risk factors for what is now called “long Covid”.
An estimated 300,000 excess deaths occurred in the US from late January through October, 2020, of which 200,000 (66%) were attributed to COVID-19. The largest increases in mortality were seen among adults aged 25–44 years and among Hispanic or Latino persons.
Disentangling T cell responses
A screen of viral protein fragments (epitopes) recognised by cytotoxic (CD8+) T cells in COVID-19 patients reveals that 90% of these epitopes are not on the viral Spike protein, and that they show almost no cross-reactivity with epitopes in seasonal coronaviruses. These findings could explain the detectable but modest CD8+ T cell responses generated by the vaccine candidates (which target the Spike protein).
Inconclusive data for an immunomodulatory drug
The JAMA journal published three studies on the use of tocilizumab (an antibody targeting the function of an inflammatory cytokine) in COVID-19 patients with pneumonia. One large study in the US suggested mortality was reduced among critically ill patients treated in the first 2 days of ICU admission. However, two randomized clinical trials from Italy and France found no reduction in mortality by day 28.
Eli Lilly announced that its antibody treatment did not appear to work in hospitalized patients, although it is confident that it may prevent progression to disease in recently diagnosed patients.
Rising hopes for older populations
AstraZeneca announced that its candidate vaccine (based on a chimpanzee adenoviral vector) triggers similar immune responses in older and younger adults, and that it triggers lower adverse events in older adults.
AstraZeneca and Johnson & Johnson will restart their clinical trials in the US after finding that serious illnesses in a couple of volunteers did not appear to be related to the vaccines.
[Evidence published between 14/10/2020 and 20/10/2020]
Genomic studies and blood type
A genome wide study confirms previous studies indicating that a gene cluster on chromosome 3 is associated with severe COVID-19 disease. The study also confirms a potential involvement of blood type genes: A would be associated to a higher risk while O would have a protective effect.
Likewise, an analysis performed in Denmark compared 7422 individuals that tested positive for SARS-CoV-2 to a reference population of over 2.2 million individuals. The findings also suggest that patients belonging to blood group O had a slightly lower risk of infection, but not of hospitalization or death.
More on antibody levels and duration
A serological study used different, parallel assays to improve the detection of antibodies to SARS-CoV-2 in the population. Results from 5882 individuals reveals that antibodies targeting the receptor binding protein of the Spike protein and another region of Spike (S2) remained detectable through 5-7 months post-onset, while antibodies targeting the nucleocapsid protein decreased. They also showed that individuals with severe disease had higher titres of virus-neutralizing antibodies than those with mild disease.
A previously reported case of SARS-CoV-2 reinfection in a 25 year-old man in Nevada was published. Reinfection was confirmed by virus genomic sequencing and the second infection (almost two months apart) was more severe. However, antibody levels were not assessed for the first infection, so no conclusions on immunity duration can be drawn. To date, it seems that reinfection is possible, but is also quite rare. It is probable that vaccines, which raise antibodies against the viral Spike protein, make us even less susceptible to reinfection, although the duration of the protection conferred by the vaccine is still not known.
A successful trial with rather disappointing
The international SOLIDARITY trial released its long-awaited interim results. None of the four treatments in the trial led by the WHO, which enrolled more than 11,000 patients in 400 hospitals around the globe, increased survival. Hope for hydroxychloroquine and the HIV treatment lopinavir/ritonavir had already faded after results from the UK trial RECOVERY. But hope remained for remdesivir and interferon beta. However, Gilead’s remdesivir had no effect in reducing mortality, even after pooling data with three other clinical trials. And interferon beta, with or without lopinavir/ritonavir, did not reduce mortality or delay the need for ventilation. Nonetheless, the international trial itself, which was set up in a very short time, is touted as an unprecedented success
A preliminary study performed in non-human primates suggests that convalescent plasma therapy is an effective strategy if donors with high level of antibodies against SARS-CoV-2 are employed and if recipients are at an early stage of disease.
Phase I/II results were published for another Chinese inactivated SARS-CoV-2 vaccine developed by the Beijing Institute of Biological Products. BBIBP-CorV is safe and well tolerated. Two doses of the vaccine induced high levels of neutralising antibody titres, even in adults above 60 years of age.
Russia has registered its second coronavirus vaccine candidate (the peptide-based EpiVacCorona), and will start large-scale trials. Early trials on 100 volunteers were said to have been successful but results have not yet been made public.
The Serum Institute of India and Bharat Biotech are expected to start Phase III clinical trials of an intranasal COVID-19 vaccine in the coming months, once they receive regulatory approval. All other candidate vaccines currently in Phase III trials are injected.
[Evidence published between 07/10/2020 and 13/10/2020]
Ten months into the epidemic, about 10% of the global population may have been infected with SARS-CoV2, according to the WHO. That’s more than 20X the number of confirmed cases.
Ventilate, ventilate, ventilate
Aerosols (drops smaller than 100 μm) containing infectious virus can travel more than 2 m and accumulate in poorly ventilated indoor air, leading to superspreading events. Hence, the importance of moving activities outdoors, improving indoor air using ventilation and filtration, and improving protection for high-risk workers, says a comment in Science.
In fact, ventilation would be another layer of defence- together with facemasks, hand hygiene, or social distancing- in the “Swiss Cheese” model, whereby each measure or layer has inherent flaws or “holes” but, when used together, considerably decrease the risk.
Contaminated surfaces: An Australian study shows that infectious virus can remain on certain surfaces up to 28 days at 20ºC (much less with higher temperatures). However, these experiments were performed in laboratory conditions, and in the dark. Other recent studies recovered almost no infectious virus from exposed surfaces in real-life conditions.
Progress in diagnostics
Rapid tests with a Nobel-Prize technique
A team led by Jennifer Doudna developed a novel diagnostic for SARS-CoV-2 based on the molecular editing tool CRISPR (for which she shared the Nobel Prize this year). The CRISPR-based diagnostic is highly sensitive, can give results in 5 minutes using a mobile phone readout, and can even quantify the amount of virus (the intensity of the fluorescent signal is proportional to the initial amount of RNA).
The value of saliva
A study shows that antibodies to SARS-CoV-2 are maintained in saliva and blood from the majority of COVID-19 patients for at least 3 months after they developed symptoms. This also means that saliva samples could be used not only for testing viral RNA (current infections) but also antibodies to the virus (past infections).
Risk factors in Sweden
A study analysing over 17,000 COVID-19 deaths in Sweden shows that being a man, having a lower income, having a lower level of education, not being married, and being born in low- or middle-income countries are factors that independently increase the risk of dying from COVID-19.
Eli Lilly announced first results for a combination of its rheumatoid arthritis drug (baricitinib) and Gilead’s remdesivir. Fewer deaths were reported among COVID-19 patients taking the combination, as compared with remdesivir alone (5.1% versus 7.8% at day 29). The effect was most pronounced in patients on oxygen therapy. Baricinitib could help modulate the cytokine storm observed in severe cases.
Monoclonal antibody cocktails
Eli Lilly also announced preliminary results for its cocktail of two monoclonal antibodies in non-hospitalised COVID-19 patients (it had previously announced promising results for a similar treatment using one antibody). The antibody combination significantly reduced the amount of virus in nasal swabs of patients after 11 days and resulted in less hospital visits for those who received the cocktail (0.9%) versus placebo (5.8%).
However, it is important to keep in mind that to date there are no phase 3 results for monoclonal antibodies, and that upscaling their production is challenging and costly.
China joins COVAX
China has announced it is joining the COVAX facility, an international initiative working to ensure all countries have access to COVID-19 vaccines. More than 150 countries have already signed. The US and Russia have not.
[Evidence published between 30/09/2020 and 06/10/2020]
If current trends continue, by next January the total number of COVID-19 deaths will reach 2.5 million. This figure could be cut to 1.8 million if every country adopts universal mask-wearing, according to recent projections.
Insights from India
A massive study of transmission dynamics in India confirms the 80/20 rule for SARS-CoV-2 transmission: 77% of cases did not transmit. The study also showed that young children transmitted the virus to close contacts of their own age. Overall, the probability of an infected person transmitting the virus to a close contact ranged from 2.6% in the community to 9% in the household. Reported cases and deaths have been concentrated in younger people than in higher-income countries, perhaps because older people in India tend to be healthier and have better access to care.
Two studies in Italy were unable to culture infectious virus from surfaces in hospital wards or emergency rooms, supporting the notion that transmission through inanimate surfaces is less frequent than previously thought.
A large analysis of obesity and COVID-19 estimates that people with obesity who contracted SARS-CoV-2 were 113% more likely to be hospitalized, 74% more likely to be admitted to an ICU, and 48% more likely to die, than people of healthy weight.
A recent genome association study identified a cluster of genes on chromosome 3 as a risk locus for severe COVID-19. A new study shows that a segment on this locus comes from Neanderthals and is carried by around 50% of people in South Asia and 16% of people in Europe today.
T cell diversity- the more, the better
A new study shows that diversity of T cell responses to SARS-CoV-2 was associated with milder symptoms of COVID-19, indicating that immunity requires recognition of multiple viral protein fragments (or epitopes). These findings could guide the design of more effective multi-peptide vaccines. The study also shows that 100% of COVID-19 convalescent individuals had T cell responses to these different epitopes, even if they had no detectable antibodies.
The promise of synthetic antibodies
Regeneron Pharmaceuticals revealed early results for its cocktail of two synthetic monoclonal antibodies that attach to the Spike protein of SARS-CoV-2 and block it from infecting cells. The cocktail reduced the amount of virus in nasal swabs and alleviated symptoms more quickly, particularly in patients who were seronegative (did not have SARS-CoV-2 antibodies) and had high viral loads at the trial’s start. The experimental drug was provided to Donald Trump, who contracted COVID-19 this week, under ‘compassionate use’.
Although synthetic antibody cocktails seem a promising treatment for mild cases, many experts worry that they may only be available to a few, given the cost and challenge of upscaling their production.
An intranasal spray developed to boost innate immune responses against common colds and flu, reduced SARS-CoV-2 viral RNA levels in nose and throat by up to 96%, when tested in ferrets. The product, developed by the Australian biotech Ena Respiratory, could provide protection against COVID-19.
Good news for older adults
A small study with older adults (over 55 years of age) shows that Moderna´s mRNA-1273 vaccine induced neutralizing-antibody titers similar to those in the 18-55 year-old group, and higher than the levels observed in plasma from convalescent patients.
[Evidence published between 23/09/2020 and 29/09/2020]
This week, the world has reached the grim milestone of one million deaths of COVID-19.
From younger to older adults
A report from the US Centers for Disease Control (CDC) provides evidence that younger adults contributed to transmission of COVID-19 to older adults. During June, the increase in SARS-CoV-2 infection among younger adults preceded the increase among older adults by 4–15 days (equivalent to 1-3 incubation periods).
Children and adolescents – lower odds of infection
A review of 32 studies concludes that children and adolescents under 20 years of age had 44% lower probability of getting infected with SARS-CoV-2, as compared with adults over 20 years of age. The difference was most marked in those younger than 10 to 14 years. However, there was not sufficient data to conclude whether transmission by children is lower than by adults.
A flawed type 1 interferon response
Two papers published in Science this week help explain why some people develop severe COVID-19 disease. Both studies reveal that up to 14% of severe cases have an impaired interferon response due to genetic errors or to antibodies against interferon itself. Type 1 interferon is one of our first lines of immune defense against viral infections.
The first study examined blood samples from almost 1,000 critically ill patients from around the world and found that 10,2% of them had antibodies that bind to and neutralize type I interferon. None of the 663 patients with mild or asymptomatic infection had those autoantibodies. Interestingly, 94% of the patients with such autoantibodies were male, which could help explain why men are more susceptible to severe disease. The second study found that 3.5% of critically ill patients carried rare mutations genes involved in the production, or function, of type 1 interferon. These findings are the first results from the COVID Human Genetic Effort, an international project including more than 50 genetic sequencing hubs and hundreds of hospitals.
Hypertension drugs: no longer in cause
A review of 19 studies confirms that drugs usually taken to reduce blood pressure (angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers) do not seem to increase the risk of developing more severe COVID-19.
More monoclonal antibodies in the pipeline
One study describes two ultrapotent human neutralizing antibodies, capable of protecting hamsters against challenge with the SARS-CoV-2 virus. The study also provides valuable information for designing antibody cocktails that circumvent viral escape mutants. Another study that isolated antibodies from COVID-19 patients found one that was particularly effective in protecting hamsters from SARS-CoV-2 infection, weight loss and lung pathology.
Novavax has started a phase 3 clinical trial in UK for its recombinant nanoparticle vaccine constructed from the full-length SARS-CoV-2 spike glycoprotein and the M-matrix adjuvant.
A total of 156 countries (64 high-income nations, including the UK, Australia, Canada, Japan and 29 European countries) have joined COVAX, in an effort to expand global access to Covid-19 vaccines. These countries represent 64% of the world population. The US, Russia and China have not joined the initiative spearheaded by the WHO, Gavi and CEPI.
[Evidence published between 16/09/2020 and 22/09/2020]
Yet another study supports the notion that much of the transmission results from a few ‘superspreader events’. By tracing contacts from over 1,000 SARS-CoV-2 cases in Hong Kong, researchers estimated that 19% of cases accounted for 80% of all local transmission. Transmission was more frequent in social settings (such as weddings, bars, and places of worship) than in households.
Rapid molecular tests
Two teams have developed molecular tests that are almost as rapid and easy to use as the antigenic tests, but have the advantage of detecting lower amounts of the virus. STOPCovid uses a CRISPR-mediated detection that can produce results in 30 minutes to an hour, with similar accuracy as the standard PCR. CovidNudge is a point-of-care PCR which requires no laboratory handling or sample pre-processing.
Progress in specific treatments for SARS-CoV-2
Proof of concept for monoclonal antibodies
Eli Lilly announced preliminary but encouraging data for its neutralizing antibody LY-CoV555. The rate of hospitalization was lower in patients who were treated with LY-CoV555 (1.7%), than in patients who received placebo (6%). The drug was well tolerated at all of the doses tested.
Help from alpacas
A Swedish group obtained an alpaca-derived antibody that targets the domain of the SARS-CoV-2 spike protein that binds to the human ACE2 receptor and is capable of neutralizing the virus in vitro. Alpacas and other camelids produce antibodies (or nanobodies) that are smaller than human antibodies, which makes them easier and cheaper to produce in high quantities.
Convalescent plasma: still not clear
A study performed in The Mount Sinai Hospital in NYC with 39 severe or critically ill patients, suggests that convalescent plasma (i.e. blood from recovered donors) may decrease the risk of requiring oxygen and improve survival in plasma recipients. In this study, only donors with high antibody levels were selected. However, the study found no correlation between the amount of neutralizing antibodies in the plasma and its effectiveness.
[Evidence published between 09/09/2020 and 15/09/2020]
Making sense of viral mutations
The analysis of almost 20,000 SARS-CoV-2 genomic sequences since December 2019 suggests that the viral mutations observed are the result of neutral evolution, rather than of selective pressure. One of the most common mutations in the viral Spike protein (the D614G mutation) has become dominant, yet there is no evidence it affects binding to the human ACE2 receptor. Importantly, the mutations observed to date should not prevent vaccines from providing global protection.
Which cells can be infected?
A ‘RNA map’ at the single cell level identifies those cells in our body that express the ACE2 receptor and other proteins that provide an entry route to SARS-CoV-2. Cells in the intestine and kidney appear highly susceptible to infection, which is consistent with clinical data. Findings also identify alternative entry paths to lung and brain cells.
Viral spread in US and Europe could have been avoided
An analysis that integrated multiple information sources, including air travel flows, disease incidence, and virus genome sequencing shows that rapid interventions successfully prevented early introductions of the virus into Germany and the USA. Therefore, intensive testing and contact tracing could have prevented SARS-CoV-2 from becoming established in the USA and Europe.
An analysis in the UK confirms that transmission from strictly pre-symptomatic infections is high (41% of cases) and that most transmission occurs in the window from 2-3 days before to 2-3 days after symptom onset.
Face masks: beyond protection?
Recent data have led to suggest that face masks may not only protect people from infection, but may also reduce the severity of disease among people who do become infected. In fact, some experts propose that, by reducing the viral load that an exposed person inhales, face masks could lead to an increase in the proportion of SARS-CoV-2 infections that are asymptomatic but that confer some level of immunity.
A Danish study finds no association between non-steroidal anti-inflammatory drugs (i.e. ibuprofen) and COVID-19 severity or mortality.
More on treatment
Plasma of recovered patients
In a multicentre, randomized clinical trial in India, with over 450 patients, convalescent plasma did not reduce mortality or progression to severe COVID-19. However, titres of neutralizing antibodies vary greatly between donors, so measuring their levels should help determine their efficacy.
The first treatment specifically designed for the new coronavirus, an antibody cocktail developed by Regeneron, will start to be tested in clinical trials.
Researchers at the University of Washington used computers to design ‘miniproteins’ that bind tightly to the SARS-CoV-2 Spike protein. More than two million candidate proteins were designed and over 100,000 were produced and tested in the lab. The best candidates were up to six times more potent in inhibiting infection, as compared to the most effective monoclonal antibodies described to date. These minibinders are also easier and cheaper to scale up.
More on vaccines
Through the nose
Preclinical studies in mice shows that an adenoviral vector expressing the whole-length S protein induces significantly higher neutralizing antibodies in the periphery and in the lungs when the vaccine is administered intranasally. The vaccine, developed by Vaxart, USA, will start to be tested in humans.
Meanwhile, China will start phase 1 trials for a potential COVID-19 vaccine administered through a nasal spray, which contains strains of the weakened flu virus with genetic segments of the SARS-CoV-2 Spike protein.
A short but important pause
The UK clinical trial of AstraZeneca's vaccine has resumed after a pause due to a possible adverse event in a woman participant who experienced symptoms consistent with transverse myelitis. This kind of event is expected when testing the vaccine in thousands of people, and the pause is a reassuring sign that the process to ensure the safety of the participants is working. Britain's regulatory agency concluded it was safe to restart. There is no word yet as to when the trial will restart in the USA.
Indirect effects of the pandemic
The pandemic is widening the gap between rich and poor countries - 69% of respondents in poorer countries reported a drop in income, compared to 45% in richer ones, shows a survey for the BBC.
[Evidence published between 02/09/2020 and 08/09/2020]
Virus in every breath?
Patients can exhale millions of SARS-CoV-2 RNA copies into the air per hour simply by breathing, according to a study in China. In contrast, viral RNA was less frequently detected on surfaces used by the patients. Although the study did not analyse infectivity, it does support measures such as enhanced ventilation and the use of face masks to minimize the risk of infection by airborne SARSCoV-2.
More on risk factors
An analysis of many studies concludes thatpregnancy is a risk factor for requiring intensive care treatment for COVID-19. Furthermore, the disease raises the risk of preterm births.
Sickle cell carriers
Carrying one copy of the sickle cell gene could increase the risk of severe COVID-19 or death and help explain why COVID19 is disproportionately killing Black Americans, according to some researchers. Up to 3 million Americans are estimated to carry one copy of the gene.
SARS-CoV-2 is normally detected in the respiratory tract. However, a Swedish study shows that patients that also have SARS-CoV-2 RNA in blood when they arrive to the hospital are seven to eight times more likely to become critically ill and die.
Immunity to SARS-CoV-2
Data from Iceland
Antiviral antibodies against SARS-CoV-2 were detected four months after diagnosis, according to a study in Iceland that used six different assays to measure antibodies in more than 30,000 people. The results also allow to estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%.
The key role of T cells
CD8+ T-cell responses might serve as a more precise marker of antiviral immunity than antibodies, concludes a study that analysed CD8+ T cell responses in 26 convalescent patients and 25 healthy donors. Notably, SARS-CoV-2-specific T cells were present even in convalescent patients with no detectable antibodies. Another study showed higher proportions of SARS-CoV-2-specific CD8+ T cells inpatients with mild disease, as compared to severe cases.
Other ‘unconventional’ T cells – namely, mucosal-associated T cells and natural killer T cells - might also play a beneficial role. Patients who had these unconventional T cells in a highly active state when admitted to intensive care were less likely to have low oxygen levels and were discharged sooner than patients whose cells were not so active.
Finally, a review on COVID-19 immunity stresses that memory B cells and T cells may be maintained even if there are not measurable levels of serum antibodies.
Treatment: lifesaving steroids
Corticosteroids can reduce mortality among critically ill patients, according to a WHO-led analysis of 7 randomized trials that included 1703 patients. The death rate at 28 days was of 32% in patients who received corticosteroids (including dexamethasone), as compared to 40% in patients who received usual care or placebo.
Phase 1 results for two more vaccines
Novavax’s NVX-CoV2373, a nanoparticle vaccine composed of trimers of the SARS-CoV-2 spike protein and Matrix-M1 adjuvant, appeared to be safe, and by day 35 elicited antibody responses that exceeded levels observed in Covid-19 convalescent serum as well as good CD4+ T cell responses.
The first results for the Russian vaccine based on adenoviral vectors and developed by the Gamaleya Institute were also published. The vaccine consists of a first shot with one type of recombinant adenovirus (rAd26-S) and a boost with another type of adenovirus (rAd5-S), 3 weeks later. The vaccine showed a good safety profile and induced strong humoral (i.e. neutralising antibodies) and cellular (CD4 and CD8) immune responses in all participants. The trial involved 76 healthy volunteers aged 18 to 60, bu there was no control group.
Nineteen public health experts laid out an ethical framework called the Fair Priority Model for the distribution of COVID vaccines, once they are available. It relies on three main values: benefiting people and limiting harm, prioritizing the disadvantaged, and avoiding discrimination. The authors argue that distributing different quantities of vaccine to different countries is not discriminatory if it effectively benefits people while prioritizing the disadvantaged.
A poll by the Spanish institution FECYT shows that 68% of respondents is willing to get vaccinated against COVID-19. Overall, vaccine trust is still high among Spanish people: most consider that vaccines are effective in preventing disease (96%) and safe (94%).
[Evidence published between 28/08/2020 and 01/09/2020]
Faster, simpler tests for detecting the virus
The SHERLOCK assay, based on uses a high-sensitivity enzymatic reporter to detect SARS-CoV-2 RNA. The test is highly specific and sensitive and should facilitate SARS-CoV-2 detection in settings with limited resources, since it does not require specialised equipment.
The U.S. FDA gave an emergency use authorization to Abbott Laboratories for a 15 min test that detects viral proteins (instead of viral ARN) and will cost 5 USD. The BinaxNOW test uses a lateral flow technology (i.e. a paper strip) to detect viral antigens from nasal swabs. Even if less accurate or sensitive than PCR tests, experts argue that these antigen tests can help to rapidly detect people who have high viral loads and are therefore potentially infectious.
COVID-19: easily missed in children
A study with 91 children in Korea that tested positive for SARS-CoV-2 during contact tracing shows that 66% had unrecognized symptoms before diagnosis and that 22% remained asymptomatic throughout the study. The duration of symptoms varied widely, from three days to nearly three weeks.
Several studies from across the world have allowed to quantify the risk of dying from COVID-19. For every 1,000 people infected with the coronavirus who are under the age of 50, almost none will die. For people in their fifties and early sixties, about five will die — more men than women. The risk then climbs steeply as the years accrue. For every 1,000 people in their mid-seventies or older who are infected, around 116 will die.
A prospective study of 651 children and young people under 19 years of age admitted to 138 hospitals in UK, concludes that severe disease was rare and death was exceptionally rare. It also indicates that children with multisystem inflammatory syndrome have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (PCR positive) or are post-acute (antibody positive). Black ethnicity was significantly associated with admission to critical care.
Advances in Treatment
A cohort study performed in 60 Spanish hospitals with 778 COVID-19 patients in hyperinflammatory state shows that tocilizumab (an antibody that blocks the inflammatory IL-6 molecule) lowered the risk of intubation and/or death in these patients. However, randomized clinical trials are needed to confirm this.
A broad-spectrum antiviral drug ?
A small peptide derived from a mouse host-defense protein exhibited potent antiviral activity against viruses that enter the cell via small vesicles called endosomes, including the H1N1 influenza virus, the avian influenza H7N9 virus, and the coronaviruses SARS-CoV-2, MERS-CoV and SARS-CoV. The P9R peptide significantly protected mice from lethal challenge by the H1N1 virus. Another advantage is that it shows low possibility of leading to drug-resistance.
Vaccines: do not rush it
Moderna announced that its mRNA vaccine induced immune responses in older adults similar to those in younger participants, offering hope that it will be effective in people considered to be at high risk of severe disease.
As the vaccine race is intensifying, many scientists warn about the risk of releasing a vaccine into the market without enough efficacy data. “A rush to register the first vaccine will make it more difficult to evaluate other vaccines that could be more effective” they say.
[Evidence published between 21/08/2020 and 27/08/2020]
Children: viral spreaders or not?
A study with 192 children with suspected or confirmed SARS-CoV-2 infection shows that the viral load in the nose and throat was highest in children in the first 2 days of symptoms, and significantly higher than hospitalized adults with severe disease. However, it should be noted that high viral RNA levels do not always mean high infectivity.
On the other hand, the Kids Corona study conducted in Barcelona this summer, with over 2000 participants, found that the basic reproduction number (R0) in summer camps was six times lower than in the general population, and that infected children generated few secondary cases. Keeping groups small and constant was key to containing transmission, in addition to hand hygiene, use of face masks and outdoors activities. Another study in the UK also shows that SARS-CoV.2 infections and outbreaks were uncommon in summer schools and that transmission occurred mainly between staff. The results emphasise the importance of controlling community transmission to protect educational settings.
Another study with over 33,000 children shows a low pooled prevalence (0.65%) of positive SARS-CoV-2 test results among children who were asymptomatic and presenting for surgical or medical care at 25 hospitals across the US throughout May 2020.
Saliva: a reliable and easier option
The Kids Corona study also showed that PCR tests on saliva were reliable and better accepted than deep nasal swabs, as confirmed by another study performed with more than 1000 specimens from almost 400 volunteers at a drive-through testing site in US.
Predictors of disease severity and mortality
Serum levels of two inflammatory molecules (IL-6 and TNF-α) are significant predictors of COVID-19 disease severity and death, according to a study by researchers at Mount Sinai, New York. The authors conclude that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.
Obesity increases the risk of death from Covid-19 by nearly 50%, according to a meta-analysis using data from many countries. The authors of the study also suggest that obese people may need higher doses of the vaccine to be protected. These findings are worrying, given that 20% of the global population is overweight or obese, and close to 66% in the UK and US.
The good news is that the survival rates of COVID-19 patients in intensive care units are drastically improving, and this is observed across all age categories, according to data from the United Kingdom.
Reinfection cases: no cause for alarm
A 33-year-old man from Hong Kong who was treated at the hospital for a mild case in March tested positive for the virus again almost five months later, when returning from Europe, but did not develop disease the second time. Genomic analysis of the virus confirms that he was infected twice. Experts agree there is no reason to panic: i) it is not clear whether he developed neutralizing antibodies during the first infection; ii) the fact that he did not develop symptoms when reinfected is suggestive of an effective immune response that, while not avoiding infection, did avoid disease; iii) the frequency of reinfections and their role in viral spread still needs to be determined.
Vaccines: better through the nose?
A single intranasal dose of Oxford’s ChAd-SARS-CoV-2-S candidate vaccine almost completely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts in a mouse model expressing the human ACE2 receptor. This is in contrast with intramuscular administration, which induces robust systemic immune responses and protects against lung pathology but does not confer sterilizing immunity (i.e. the virus does manage to infect).
Another vaccine that also uses an adenovirus (Ad5) encoding the SARS-CoV-2 spike protein, protected rhesus macaques from infection when given in either nasal or injected form. Although intranasal vaccination elicited less systemic antibodies and cellular responses than intramuscular vaccination, it conferred effective protection against SARS-CoV-2 infection. The authors argue that an intranasal vaccine might allow people to vaccinate themselves.
A table to evaluate the risk of transmission
The risk of transmission goes beyond the simple safety distance rule – it also depends on other factors such as air flow, viral load, and contact duration with other people. A table incorporating all these factors allows to better evaluate the risk of transmission in different settings and activities.
[Evidence published between 31/07/2020 and 20/08/2020]
A milder virus variant?
SARS-CoV-2 variants with a particular deletion (∆382) in its genome have been detected in Singapore and other countries. A study with 278 patients (22% of which were only infected with the variant form) suggests that it may be associated with a milder infection. However, further studies are needed to understand the clinical and epidemiological features of these viral variants.
Viral load in asymptomatic individuals and children
A study with 300 individuals in a community center in South Korea shows that the viral load in asymptomatic individuals was similar to symptomatic patients.
Similarly, an analysis suggests that children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx compared with older children and adults. However, these studies measured viral nucleic acid, rather than infectious virus.
A prospective cohort of COVID-19 patients followed during 12 weeks shows that most (74%) had persistent symptoms and that a more holistic approach focussing on rehabilitation and general well-being is necessary.
The persistent symptoms included fatigue and brain-fog. In this sense, a prospective brain MRI imaging study in 60 recovered COVID19 patients found micro-structural or functional abnormalities in 55% of patients at 3 months, as compared with healthy controls.
A UK report provides new evidence on excess weight as major and independent risk factor for COVID-19. A cohort study observed an elevated risk even at a modest weight gain. The mechanisms may involve impaired glucose and lipid metabolism.
Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England, according to a population-based cohort study. The risk of dying from COVID-19 was 3.5 times higher for people with type 1 diabetes, and 2 times higher for people with type 2 diabetes, as compared to non-diabetic patients.
Kidney problems may particularly impact COVID-19 patients of African ancestry carrying a high-risk APOL1 gene variant , according to some experts. Furthermore, a study on COVID-19-associated multisystem inflammatory syndrome in children in the US reveals that Hispanic and black patients accounted for the largest proportion (73.6%) of reported cases.
Mounting evidence for strong and lasting immunity
SARS-CoV-2 elicits robust, broad and highly functional memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19, according to a study published in Cell. Importantly, SARS-CoV-2-specific T cells were detectable in exposed family members that were antibody-negative, and in convalescent individuals who had asymptomatic or mild COVID-19.
In fact, a series of new studies are starting to see encouraging signs of strong, lasting immunity, even in people that developed only mild symptoms of COVID-19. One of these studies detected stable levels of IgG not only in blood but also in saliva (meaning an effective mucosal immune response) of COVID-19 recovered individuals, up to 4 months after they developed symptoms. Another study detected stable levels of antibodies specific for different viral proteins up to 3 months after infection, even in asymptomatic individuals.
A research team has engineered a soluble ACE2 receptor with enhanced affinity, which could act as a decoy by binding to the virus before it binds to host cells. This decoy receptor could be used as COVID-19 therapy.
The preclinical results for two of the leading vaccines, which are already in clinical trials, have been published. Vaccination with Oxford’s ChAdOx1 nCoV-19 induced a good antibody and T cell response in rhesus macaques. Vaccinated animals challenged with the virus had lower viral loads as compared with control animals, and did not develop pneumonia. No adverse effect related to antibody production was observed.
One single shot of the Ad26 vaccine (developed by Janssen) in non-human primates induced robust neutralizing antibody responses and provided complete or near-complete protection in upper and lower respiratory tract, following infection with SARS-CoV-2. The neutralizing antibody titres elicited by the vaccine correlated with protective efficacy.
Novavax announced promising phase I data for their recombinant vaccine coupled to a saponin-based adjuvant (MatrixM). Two doses of the vaccine were well tolerated and induced neutralizing antibodies and T cell responses in all participants. Novavax is one of the vaccines funded by operation Warp Speed.
Russia has declared a COVID-19 vaccine ready for use, despite international concern that it just began Phase 3 trials last week. The vaccine, developed by the Gamaleya Institute in Moscow with assistance from Russia’s Defense Ministry, uses an adenoviral vector to express the SARS-CoV-2 S protein. Russian scientists haven’t published any scientific information about how the vaccine has performed in animal tests or in early-stage human studies.
[Evidence published between 24/07/2020 and 30/07/2020]
Six months ago, on January 30, the WHO declared the new coronavirus a public health emergency of international concern, at a moment when there were less than 100 cases and no deaths outside China.
More on the origins of SARS-CoV-2
Although how, when or where exactly the new coronavirus jumped to humans remains a mystery, a new genomic study suggests that the coronavirus lineage that gave rise to SARS-CoV-2 diverged from related viruses 40-70 years ago and has been circulating in bats for decades. The study does not discard the hypothesis that a pangolin or another mammal served as intermediary host, but it does suggest that SARS-CoV-2 did not recombine with pangolin coronaviruses.
More on its transmission
A study with 116 deliveries by COVID-19-positive mothers shows that transmission of the virus to the baby is unlikely to occur if correct hygiene precautions are undertaken. Allowing newborns to share room with their mothers and breastfeed is safe when parents adopt the adequate protective strategies.
A major COVID-19 outbreak in a high school in Israel was associated with an extreme heatwave that led to exemption from using facemasks and to continuous air conditioning.
A genomic analysis shows that the outbreak on the Diamond Princess cruise ship (which resulted in around 700 infected people) originated from one single individual who was infected when boarding. Viral transmission occured during recreational mass-gatherings and among people who shared cabins through mass-gatherings in recreational areas and among passengers who shared cabins during the quarantine.
People at risk
In the Americas, three out of ten people – or nearly 325 million – are at increased risk of developing severe COVID-19 illness due to underlying health conditions, says the Pan American Health Organisation (PAHO).
In the US, a multistate telephone survey of symptomatic adults who tested positive for SARS-CoV-2 infection but were not hospitalised, indicates that 35% had not returned to their usual state of health when interviewed 2 to 3 weeks after testing. One of five young adults with no chronic medical conditions suffered from long-term effects.
Another study with a cohort of German patients recently recovered from COVID-19 infection revealed heart inflammation in 60% of the patients, regardless of pre-existing health conditions or disease severity of the disease.
Mortality can be attenuated
An analysis of data from 169 countries shows that the mortality rate of COVID-19 can be attenuated by increasing testing, improving government effectiveness and increasing hospital beds
Some people who have never been infected by or exposed to the new coronavirus have antibodies that recognise a region of the viral spike protein called S2, which is conserved among cold coronaviruses (HCoVs) and SARS-CoV-2. The study also shows that these antibodies can neutralise SARS-CoV-2 and are more frequently found in children and adolescents.
Likewise, T cells of the immune system have been detected in individuals that have never been exposed to SARS-CoV-2. A study published this week in Nature detected SARS-CoV-2 reactive CD4+T cells in 83% of patients with COVID-19, but also in 35% of healthy individuals. These T cells recognised a region of the viral S protein that is also present in common cold coronaviruses. The role of these pre-existing SARS-CoV-2 cross-reactive T cells in determining the clinical outcome of the disease is not clear yet.
An antibody originally obtained in mice reduced SARS-CoV-2 levels in the lungs and prevented pulmonary pathology in a mouse model of COVID-19. The antibody efficiently binds to the receptor binding domain of the viral spike protein and neutralizes SARS-CoV-2.
This week, four studies published this week provide further evidence on the drug’s lack of efficacy in preventing or treating COVID-19.
A multicenter, controlled trial in Brazil involving hospitalized patients with mild or moderate COVID-19 shows that the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. In addition, the RECOVERY trial posted its results with 1561 hospitalized patients who received hydroxychloroquine compared with 3155 patients who received usual care. The drug was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.
These results are supported by two preclinical studies. One study, performed with rhesus macaques infected with SARS-CoV-2, shows no therapeutic or prophylactic effect of hydroxychloroquine, with or without azithromycin. Another one shows that although chloroquine inhibits SARS-CoV-2 spread in kidney cell lines, it does not block SARS-CoV-2 infection in a lung cell line, indicating that the drug targets a pathway that is not operative in lung cells and is unlikely to protect against SARS-CoV-2 spread in and between patients.
A vaccine composed by the mRNA encoding for the SARS-CoV-2 receptor binding domain and encapsulated by lipid nanoparticles (mRNA-LNP) elicited robust neutralizing antibodies against SARS-CoV-2 as well as a cellular response in mice and non-human primates. The ARCoV vaccine, developed by a Chinese team, can be stored at room temperature for at least one week. It is currently being evaluated in phase 1 clinical trials.
Non-human primates vaccinated with Moderna’s mRNA vaccine were protected against lung inflammation and damage when exposed to the virus. Vaccinated animals showed a good neutralising antibody response and a good CD4 T cell response (but a low or undetectable CD8 T cell response).
[Evidence published between 17/07/2020 and 23/07/2020]
Synchronizing intermittent lockdowns across Europe could divide by half the lockdown periods needed to end community transmission in the continent, according to a study. On the contrary, if well-connected countries end their interventions prematurely, a resurge in cases could occur up to 5 weeks earlier.
COVID-19 transmission and children
A South Korean study that included 59,073 contacts of 5,706 COVID-19 index patients shows that 11-8% of household contacts had COVID-19, versus 1.9% of non-household contacts. It also shows that older children (10-19) may spread disease at rates comparable to adults, though younger children may be less likely to transmit. However, the study only analysed patients with symptoms. It is still not clear how efficient are asymptomatic children in spreading the virus.
More on antibody levels
A study with 34 patients with mild COVID-19 symptoms describes a rapid decay of SARS-CoV-2 antibodies in some of these patients, leading the authors to raise caution regarding herd immunity and vaccine durability.
However, the threshold needed for protection is not yet known, and a slow decline of antibodies over time is to be expected. In fact, another study with 19,860 individuals in New York City shows that the vast majority of infected individuals with mild to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, that titers are relatively stable for at least three months, and that the titers of anti-spike antibodies significantly correlate with neutralization activity.
Boosting frontline defences
The British company Synairgen announced promising but preliminary results for an inhaled form of interferon beta in reducing the risk of severe COVID-19. In fact, a series of recent papers suggests SARS-CoV-2 disables interferons, one of the body’s frontline defences against a virus, and at least five studies have found that interferon treatment or pretreatment has a protective effect in cells and in mice infected with SARS-CoV-2. Ongoing trials are testing interferons as prophylaxis or early treatment. One of them, just published, shows that IFN-a2b reduced in-hospital mortality but only when administered within the first five days upon hospital admission.
Two potent neutralizing antibodies, which recognize non-overlapping sites of the SARS-CoV-2 Spike protein, protected mice and rhesus macaques from SARS-CoV-2 infection and disease.
Encouraging Phase 1 results for two adenovirus-vectored vaccine candidates
The Phase 1 trial for the Oxford vaccine candidate, based on a chimpanzee adenovirus vector (ChAdOx1 nCoV-19), showed an acceptable safety profile and induced neutralising antibodies in more than 90% of the 1077 participants. Antibody levels were further increased in a small group that received a second dose of the vaccine, 28days later. Virus-specific T cell responses were also observed in most participants.
Another vaccine candidate using a human adenoviral vector developed by CanSIno in China also induced neutralizing antibodies and T cell responses in most people after a single dose, with a good safety profile. Older people (aged >55 years) responded less well, which means they may need a second dose.
It is still not known whether these vaccines can prevent infection or disease. This requires phase 2 and phase 3 trials, which have already started for some candidates. The Oxford/Astra Zeneca vaccine is being tested in Brazil, together with China’s Sinovac inactivated virus vaccine. The country has now approved human trials for a third COVID-19 vaccine (mRNA vaccine co-developed by Pfizer and BioNTech).
An initiative to speed-up vaccine efficacy results
The advocacy group, 1Day Sooner, has sent an open letter signed by 15 Nobel laureates and 100 other prominent researchers, ethicists, and philosophers, urging the U.S. government “to undertake immediate preparations for human challenge trials”, aimed at vaccinating young people- who are less likely to suffer severe disease from COVID-19 - and subsequently exposing them to the virus under controlled conditions.