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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.
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.
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).
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.
A model-based study indicates that the majority of infections may be attributable to silent transmission from a combination of presymptomatic and asymptomatic individuals. The model also indicates that over 1/3 of these ‘silent infections’ must be isolated to suppress a future outbreak below 1% of the population
More on risk factors
Ethnicity and death
Two more studies support the disproportionate toll of COVID-19 on certain ethnic groups. The OpenSAFELY study in UK analysed factors associated with COVID-19 death in 17 million patients. Compared with people of white ethnicity, Black and South Asian people were at higher risk even after adjusting for other possible factors. Along the same lines, the US CDC published the analysis of 10,647 COVID-19 deaths. They found that a majority were aged ≥65 years and most had underlying medical conditions. However, among those that died under the age of 65, most were Hispanic (35%) or non-white (30%), as compared with only 13% of white, non-Hispanic decedents.
A previous genetic study had suggested a strong link between blood type and the risk of developing severe disease. However, two new studies that analysed thousands of cases (one from Massachusetts and one from Columbia University) indicate that this link, if it exists, is weak. Although both studies found that Type O people were slightly at less risk of getting infected, no significant association between blood type and risk of developing severe disease was found.
Not only a respiratory disease
Other studies published this week confirm that SARS-CoV-2 infection may be associated with neurological syndromes, including acute disseminated encephalomyelitis and inflammation of the brain’s smell center. In fact, as detailed in this review, COVID-19 can result in several extrapulmonary manifestations, including thrombosis, heart complications, kidney injury, and gastrointestinal symptoms, which result either from direct viral infection of other tissues expressing the ACE2 receptor, or as a result of indirect injury due to endothelial damage and inflammation.
Indeed, a series of autopsies published this week support the notion that the organ inflammation and dysfunction observed in fatal COVID-19, is not due to direct damage caused by the virus, but is rather a consequence of immune-mediated damage. In fact, the distribution of viral RNA did not map with the most affected tissues and organs.
An Italian team followed a cohort of 143 patients recovered from COVID-19, during 2 months after their hospital discharge. 87% of recovered patients had persistence of one or more symptoms, including fatigue, breathing difficulty, joint and chest pain.
Waning antibodies may not mean waning immunity
Using serum samples from 65 confirmed cases of SARS-CoV-2 infection collected up to 3 months after symptom onset, a UK team shows that >95% of cases develop neutralizing antibodies beyond 8 days after symptom onset and that antibody levels depend on disease severity. However, declining antibody titres were observed during the follow-up period, particularly in individuals who had milder symptoms. These findings suggest a transient antibody response, similar to that observed with common cold seasonal coronaviruses.
However, waning antibodies does not necessarily mean loss of immunity. The level of antibodies required to confer protection is still not clear, and it may not only be a matter of antibody quantity but of quality (the affinity with which the antibody binds to the virus). In addition, several studies support the role of T cells (which are responsible for activating antibody-producing B cells) in maintaining long-term immunity to the virus, regardless of antibody levels. In particular, a team in Singapore demonstrated the presence of T cells recognizing multiple regions of the nucleocaspid (NP) protein of the SARS-CoV-2 virus in COVID-19 convalescent patients. They also showed that patients who recovered from SARS in 2003 still possess long-lasting memory T cells against the virus. Importantly, they also detected SARS-CoV-2 specific T cells in a high percentage of individuals with no history of previous exposure to SARS or to the new coronavirus. These cells recognised protein fragments conserved amongst many animal betacoronaviruses. These results are encouraging, since they suggest we can generate long-lasting and possibly cross-reactive T cell immunity to multiple coronaviruses.
The Phase 1 results of the Moderna SARS-CoV-2 vaccine have been published and show good immune responses generated after two vaccinations, 28 days apart. Anti–SARS-CoV-2 immune responses (nAbs) were observed in the 45 health participants. No safety concerns were identified although some systemic adverse effects such as fever were observed, particularly in the high dose group. Moderna will start a Phase 3 study in 30,000 patients on July 27. Pfizer and BioNTech also plan to start a large study with their mRNA vaccine candidate by the end of the month.
The pandemic’s indirect death toll
According to a modelling study, deaths due to HIV, tuberculosis, and malaria over 5 years could increase in high-burden countries by up to 10%, 20%, and 36%, respectively, compared with if there was no COVID-19 pandemic.
A dominant viral variant
A SARS-CoV-2 variant has become the dominant pandemic form, according to a study. This variant (dubbed G614) has one amino acid change in Spike, the viral protein that allows entry into human cells. The authors argue that the consistent increase of G614 at regional levels may indicate this variant has a fitness advantage. Patients infected with this variant seem to have higher viral loads, and laboratory studies suggest it may replicate better. However, there is no evidence for the moment that this amino acid change makes it more transmissible or lethal.
The debate over aerosol transmission
Over 200 scientists sign an open letter urging the WHO to address the potential transmission of SARS-CoV-2 via small aerosol droplets (which travel farther and remain longer in the air than respiratory droplets). They argue that aerosol transmission could explain several "super-spreading" events, including the infection of diners at a restaurant in China who sat at separate tables or of choir members in the US who took precautions during rehearsal. However, a group of more than 30 international experts advising the WHO “has not judged the existing evidence sufficiently convincing to consider airborne transmission as having an important role in COVID-19 spread".
The ENE-COVID study in Spain, which measured SARS-CoV-2 antibodies in over 60,000 participants across the country, announced the results for the second round of testing. Overall, 5.2% of the population had IgG antibodies against SARS-CoV-2 (barely higher than the 5% prevalence detected in the first round). Again, Madrid was the region with the highest prevalence (10%). Regarding age, antibody prevalence was lower in babies, children and young people. A majority (80%) of the participants who reported having had a positive PCR test more than 2 weeks ago presented IgG antibodies.
Another seroprevalence study performed in Geneva indicates that, in early May, 10.8% of the city’s population had IgG antibodies against SARS-CoV-2.
The major genetic risk factor for severe COVID-19 (a segment of 50 kb within a gene cluster on chromosome 3) is inherited from Neandertals, according to a non-peer-reviewed study. This segment occurs at a frequency of 30% in South Asia and 8% in Europe. These intriguing findings have yet to be explained but could be related to a strong (maybe too strong?) immune response to viruses, according to some scientists.
Quick, effective antibody responses
Antibodies capable of neutralizing the virus are generated as early as 8 days after diagnosis, according to an analysis that followed the antibody response in 12 COVID-19 patients from 8 to 69 days after diagnosis. By screening over 4,000 antibody-producing B cells from these patients, the research team isolated 255 SARS-CoV-2 antibodies from different time points as early as 8 days post-diagnosis. Of these, 28 potently neutralized the virus. The antibodies used a broad spectrum of variable genes (those that recognises the virus) and did not require many changes (somatic mutations) to achieve this neutralizing activity.
Narrowing down the drug candidates
WHO announced that it was stopping its trials of hydroxychloroquine and the HIV combination drug lopinavir/ritonavir in hospitalised patients with COVID-19 after the medications failed to reduce mortality.
Pfizer published its phase 1 results with the mRNA candidate vaccine it is developing with BioNTech. The vaccine triggered a good level of neutralizing antibodies in healthy volunteers, although it caused fever and other moderate side effects at higher doses.
SARS-CoV-2 infection in animals
Pigs and chickens could not be infected by SARS-CoV-2, whereas fruit bats showed characteristics of a reservoir host, according to an experimental study. The study also showed that the virus replicates efficiently in ferrets although they do not develop the disease.
Lessons from the Italian town of Vo’
Vo’, in northern Italy, successfully managed to contain the epidemic by testing almost all of the 3,200 people living in the town for SARS-CoV-2 infection at two timepoints: at the start of the quarantine and fifteen days later. Findings reveal that 42.5% of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic (i.e. did not have symptoms at the time of swab testing and did not develop symptoms afterwards). The study also found similar viral loads in symptomatic and asymptomatic individuals, suggesting they have a similar potential for transmission.
Infections in the USA: multiply by ten?
The number of coronavirus infections in many parts of the USA is more than 10 times higher than reported, according to data from antibody surveys released by the CDC. The survey includes people who had blood specimens taken between March and April for reasons unrelated to COVID-19, across 10 sites in different states.
The CDC also reported data collected through a telephone survey of 350 adults who tested positive for SARS-Cov-2 infection. Only half recalled having had contact with a COVID-19 case, and most contacts were a family member or a work colleague. About one third said they had not recovered their “normal” state of health three weeks after testing positive.
Neurological and neuropsychiatric complications
A UK study reports 125 COVID-19 cases with some kind of neurological or neuropsychiatric complication. The most common brain complication observed was stroke, which was reported in 77 patients. Almost one third of the patients showed signs of confusion or changes in behaviour.
Children: a large European study
Researchers looked at 582 children that tested positive for COVID-19, aged from three days to 18 years and across 25 European countries. A quarter had underlying health conditions. More than half of the children studied were admitted to hospital, and 8% needed treatment in intensive care. Children co-infected with other respiratory viruses were more likely to be admitted to intensive care. Of the four deaths during the study (0.69%), none were in children under 10, and two of those who died had pre-existing health conditions.
Immunity: higher than antibody tests suggest?
Researchers from the Karolinska Institute in Sweden systematically studied T cells (which orchestrate the immune response and antibody production) in a large cohort of unexposed individuals as well as exposed family members and individuals with acute or convalescent COVID-19. SARS-CoV-2-specific T cells were detectable in individuals that developed no or mild COVID-19 symptoms, even in those who had no detectable antibodies. These results suggest that immunity to COVID-19 could be higher than antibody tests have shown.
In fact, seroconversion in asymptomatic patients might take longer, according to a South Korean study that found neutralizing antibodies in completely asymptomatic patients eight weeks after PCR diagnosis.
Discouraging results for an HIV drug
Lopinavir-ritonavir, an HIV drug, does not provide clinical benefit in hospitalised COVID-19 patients, according to a statement from the UK-led RECOVERY trial. There was no significant difference in the mortality or in the risk of progression to mechanical ventilation or length of hospital stay in the treated group as compared to the non-treated group.
The Recovery trial was launched in March to test the efficacy of: dexamethasone (a corticosteroid), lopinavir-ritonavir (an HIV drug), hydroxychloroquine (an antimalarial drug), azithromycin (an antibiotic), tocilizumab (an anti-inflammatory drug) and convalescent plasma (collected from COVID-19 recovered donors).
The trial has shown that dexamethasone reduces mortality in critically ill patients, while hydroxychloroquine and lopinavir-ritonavir provide no clinical benefit.
On another more positive note, a study from New York finds that people with HIV who contract Covid19 do not have worse outcomes than people without HIV.
China pushes ahead with its vaccines
China has approved CanSino’s adenovirus vaccine for military use for the next year, according to the New York Times coronavirus vaccine tracker, while the Sinopharm (inactivated virus) vaccine is starting phase III trials.
How to avoid a second wave
A model developed to measure the relevance of non-pharmaceutical interventions (i.e. not involving vaccines or drugs) shows that deconfinement must be gradual and that individual behaviour (maintaining social distancing, use of face masks, hand hygiene) is key to avoiding future waves.
Miniature human organs to study viral infection
A study with cells and organoids derived from human stem cells shows that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection. Other cell types that also express the ACE2 receptor, such as endothelium, macrophages, and cortical neurons show low or no permissiveness to infection, suggesting there are other factors involved in viral entry (for example, the TMPRSS2 surface protein). The results obtained with pancreatic beta cells add to evidence suggesting the new coronavirus may trigger diabetes, although further studies are needed.
Detecting early transmission
Italian scientists have found traces of SARS-CoV-2 in wastewater collected from Milan and Turin in December 2019, suggesting the virus was already circulating in northern Italy before China reported the first cases. However, it does not automatically imply this was the source of the large epidemic in Italy, or if there were later introductions into the country. Along these lines, an analysis performed with samples from blood donors in Lodi, northern Italy, reveals that five samples from mid-February tested positive for SARS-CoV-2 antibodies, suggesting that the virus was already circulating a few weeks before the first patient was identified.
In the United States, a spike in Influenza like illness (ILI) suggests that there were over 8.7 million new undiagnosed SARS-CoV-2 infections between March 8 - 28, 2020.
Asymptomatic and mild infections: high percentage, less antibodies?
An analysis of 5,484 contacts of SARS-CoV-2 cases in Lombardy, Italy, reveals that roughly half of the contacts became infected. However, 73.9% of all infected individuals aged less than 60 years did not develop symptoms. The risk of symptoms increased with age - 6.6% of infected subjects older than 60 years had critical disease.
The blood donor study mentioned above also revealed that 28% of blood donors recruited between 18 March and 6 April, had been infected by the virus, but most did not develop symptoms or developed only mild symptoms. They also had lower levels of SARS-CoV-2 specific antibodies as compared to convalescent patients, a finding that is confirmed in several other studies:
A Chinese team studied 37 individuals who were diagnosed by RT–PCR for SARS-CoV-2 infection but without any relevant clinical symptoms. Compared to age and sex-matched patients with mild symptoms, the asymptomatic group had lower antibody levels in the acute phase of the infection. Two months after leaving the hospital, antibody levels decreased in both groups and 40% of asymptomatic individuals became seronegative for IgG antibodies.
Another study with 149 convalescent PCR-confirmed patients (most with mild symptoms) shows that most did not have high levels of neutralizing antibodies. Nevertheless, rare but recurring antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
T cells: a better indicator of viral exposure?
Detecting T cells specific for the virus may be a more sensitive indicator of SARS-Co-V-2 exposure than antibodies, according to a study. The researchers investigated humoral (antibodies) and cellular (T cells) immune responses against SARS-CoV-2 in seven households with at least 1 known positive Covid-19 case. Six of eight household contacts had blood samples with measurable T-cell responses, but no measurable antibodies.
Treatment with convalescent plasma
A study with 20,000 hospitalized patients that received COVID-19 convalescent plasma provides evidence that it is safe, and shows some effectiveness in reducing mortality, although it was not a clinical trial.
Indirect impact on cancer mortality
The COVID-19 crisis could cause 10,000 excess deaths from colorectal and breast cancer in the United States due to interruptions in diagnosis and treatment.
The epicentre is in Latin America
Brazil and Mexico, along with the rest of Latin America is now accounting for half of global COVID-19 deaths (and likely more than that). Brazil’s total death toll has surpassed Britain to become the 2nd worst-affected country by COVID-19 in the world after the USA.
The importance of keeping distances…
A modelling study with data from over 40,000 participants in UK, shows that moderate physical distancing can reduce the proportion of cases that would need to self-isolate and of contacts that would need to be traced, in order to control SARS-CoV-2 transmission.
… and using face masks
An analysis of transmission clusters in Japan identified 22 probable primary case-patients for the clusters: most were 20–39 years of age and presymptomatic or asymptomatic at virus transmission.
Airborne transmission represents the dominant route to spread the disease, and the use of face masks shaped pandemic trends in Wuhan, Italy and New York City, according to a study .
Global population at risk
About one in five individuals worldwide could be at increased risk of severe COVID-19 disease if they become infected, due to underlying health conditions. This risk however varies considerably by age. These estimates do not include socioeconomic factors, but they do provide a starting point for considering the number of individuals that might need to be protected or vaccinated worldwide.
Children: less susceptible to infection?
According to age-based transmission models, people under 20 years of age are at half the risk of SARS-CoV-2 infection than those over 20. Only 21% of those aged between 10 and 19 are likely to show symptoms, compared with 69% of people over 70 years of age. The author’s modelling also found that school closures had little effect on stopping viral spread. Similarly, a seroprevalence study in Geneva shows that antibody prevalence was significantly lower in children under 10 years of age or adults over 64 years of age.
On the other hand, the Kids Corona study by Hospital Sant Joan de Déu reveals that children have a prevalence of SARS-CoV-2 antibodies similar to that in adults, but most develop very mild symptoms. The study followed 724 children with a COVID-19 positive parent.
In any case, there is mounting evidence that healthy blood vessels protect children from serious effects of COVID-19, such as stroke.
A cheap corticosteroid to reduce mortality?
Dexamethasone, an anti-inflammatory corticosteroid, seems to reduce COVID-19 mortality in critically ill patients, according to an announcement by the UK Recovery trial. For patients on ventilators, it cut the risk of death from 40% to 28%. For patients needing oxygen, it cut the risk of death from 25% to 20%. However, the data have not been published.
Other news on treatments
Regeneron has launched clinical trials of an antibody cocktail for treating COVID-19. It will be tested as a therapeutic agent for COVID-19 patients and as a preventive therapy in high-exposure-risk groups.
Meanwhile, the US Food and Drug Administration has withdrawn an emergency approval for use of hydroxychloroquine as Covid-19 treatment .
Sleep during confinement
An online survey in Switzerland, Germany, and Austria and a survey with university students in the USA reveal that, overall, during the lockdown people had healthier sleeping routines, although the quality of their sleep was lower. Exposure to daylight and exercising may help increase sleep quality in these situations.
Mice for testing treatments and vaccines
Mice that express the human ACE2 receptor develop pneumonia when exposed to SARS-CoV-2 and provide a good model to evaluate therapies and vaccines against COVID-19.
Restrictions including shelter orders and business closures prevented around 285 million cases in China and 60 million in the US, according to researchers at the University of California, Berkeley. Another study from Imperial College London estimated that strict shutdowns may have saved 3 million lives across 11 European countries.
Residual waters: an early alert
A retrospective analysis of residual waters of Barcelona shows that by January 15 there were detectable levels of the virus in the samples – 40 days before the first case was reported, according to University of Barcelona researchers.
Diagnosis by dogs?
The sweat odour of COVID-19-infected persons is different and can be detected by dogs, according to a study that has not yet been peer-reviewed.
Male hormones and COVID-19
All the epidemiological data confirm that COVID-19 mortality is higher in men than in women. There are several possible reasons for this, but an article in Science points to androgens as a major suspect. In the prostate, androgens induce expression of TMPRSS2, one of the molecules used by the virus to infect human cells. It is still not clear if this also happens in the lung, but a study in Italy showed that patients on androgen-deprivation therapy (ADT) were less to be hospitalized and to die. Another couple of studies associated baldness with severe disease in men, and the analysis of data from hundreds of male COVID-19 patients in UK showed a correlation between androgen levels in blood and severity of disease. Several veteran hospitals have started clinical trials with an androgen-suppressing drug in COVID-19 patients.
A study with macaques indicates that early initiation of remdesivir treatment in COVID-19 patients can prevent progression to pneumonia.
BTK is a protein (tyrosine kinase) involved in the activation of macrophages, which are part of our first line of immune defence. A study with a small number of patients with severe COVID-19 shows that treatment with a BTK inhibitor (acalabrutinib) can be beneficial in these patients. These results need to be confirmed with larger, controlled trials.
Three big trials, no efficacy in COVID-19 treatment or prevention.
Recovery, the largest trial yet, showed that treatment with hydroxychloroquine had no benefit for patients hospitalized with Covid-19. Mortality rates were similar among the over 1,500 patients who received hydroxychloroquine and the more than 3,100 patients who did not (25.7% and 23.5%, respectively).
Two other trials show that hydroxychloroquine is not effective in preventing the disease either. The first study, performed in USA and Canada, sent drug or placebo by mail to over 800 close contacts of confirmed cases. Twelve per cent of those that took the drug developed the disease, versus 14% of those who took the placebo.
The second study was performed in Barcelona’s Germans Trias i Pujol Hospital with more than 2300 people exposed to the virus. There was no significant difference between the number of people in each group who developed COVID-19, according to an announcement of trial leader Oriol Mitjà to Science .
A first controlled trial with convalescent plasma as therapy for COVID-19 showed no clinical benefit, although the number of patients was small.
The Imperial College is starting clinical trials for its “self-amplifying” mRNA vaccine in June, with 300 volunteers. If safe, it will conduct a 6,000-participant phase in October to test the vaccine’s effectiveness. This vaccine would require smaller doses than Moderna’s mRNA vaccine and less costly manufacturing facilities. The institute is creating an enterprise called VacEquity Global Health to make its vaccine available at the lowest possible cost in Britain, as well as in low- and middle-income countries.
The Oxford group has said it will start testing its vaccine in Brazil, in collaboration with Sao Paulo’s University. They will first test it in 1,000 highly-exposed volunteers.
The World Health Organisation has published a draft landscape on COVID-19 vaccines. There are currently 133 vaccines in development. Ten leading vaccines are already in human trials.
More evidence on the natural origin of the virus
An international team that investigates bat coronaviruses published the largest analysis to date on these viruses. They examined sequences from 781 coronaviruses isolated from bats in China, one third of which had not been described. They confirm that horseshoe bats are an important reservoir of SARS-related viruses. A few weeks ago, the USA government announced it was cutting funds for the project.
A phylogenetic analysis of coronaviruses from bats, pangolins and humans reveals that these viruses are subject to similar evolutionary constraints despite infecting different host species. The findings also show that SARS-CoV-2 acquired the motif that allows it to infect human cells through recombination with a pangolin coronavirus.
Multiple introductions in US or Europe
SARS-CoV-2 arrived more than once in USA or Europe before starting large outbreaks. For example, the first case detected in Seattle does not seem to have initiated the country’s epidemic. This means there was a lost time window, where case identification and contact tracing would have made a great difference.
The epidemic in New York mainly resulted from multiple cases that arrived from Europe or other regions in the country, and not from China, according to an analysis. The results also indicate there was community transmission in NY by mid-March.
The Swedish case
Swedish epidemiologist Anders Tegnell has acknowledged that the country’s strategy resulted in many Covid-19 deaths and that not enough was done to stop the virus. Last week, Sweden had the highest mortality per capita worldwide.
A review estimates that 40-45% of infections are asymptomatic but that they can transmit the virus to others for up to 14 days. Even asymptomatic infections may be associated with lung abnormalities, as detected by computed tomography
Another study confirms the importance of physical distancing of 1 m or more, face masks and eye protection in preventing SARS-CoV-2 transmission in public and health-care settings
Genetic risk factors
A European team performed the first genome wide analysis with almost 2,000 Italian and Spanish patients in order to identify genes associated with a higher risk of developing severe Covid-10. They found that the patients with A-type blood were at higher risk of developing respiratory stress, while O-type blood was protective. The reasons for this are still unclear. They also identified a cluster of six genes on another chromosome, associated with severe disease.
Chloroquine: The WHO announced it will continue testing hydroxychloroquine, after it announced last week it was temporarily halting trials as a result of a paper published in The Lancet. The study has raised major concerns regarding the dubious origin of the data used, provided by the US-based company Surgisphere. Two other studies that also used data from Surgisphere are under scrutiny: one published in NEJM on the risk -or not- of certain hypertension drugs and another preprint on ivermectin as treatment for COVID-19.
In turn, a placebo-controlled trial across the United States and Canada did not show any protective effect of hydroxycholoruine when given as preventive treatment otopeople exposed to the virus (contacts of confirmed cases).
The cost of seven days…
A Columbia University study estimates that if the U.S. had begun imposing social distancing measures one week earlier, about 36,000 deaths from Covid-19 could have been avoided .
On a ship:
On a cruise ship to Antarctica, 128 of the 217 passengers and crew tested positive for SARS-CoV-2 by PCR (which detects active infections) but the great majority (81%) were asymptomatic. One patient (0.8%) died of the disease.
Nasal epithelium is the first point of contact for SARS-CoV-2. A study shows that young children have lower levels of the ACE2 receptor (the molecule the virus uses to infect the cell) than adolescents or adults. This could in part explain why covid-19 is less prevalent in children.
Beyond the lungs
An autopsy series with Covid-19 patients reveals the presence of SARS-CoV-2 in multiple organs, including the lings, pharynx, heart, liver, brain and kidneys. This would help explain the kidney injury observed in some patients. Another study in the laboratory, with human brain organoids, shows that the virus can infect neurons in the cerebral cortex
Two major SARS-CoV-2 lineages were circulating in Wuhan at the beginning of the outbreak. A study with data from over 300 Covid-19 patients indicates that both lineages exhibited similar virulence and that the disease outcome depended on host factors such as age and immune status.
Immunity to the virus
Science publishes a study with macaques showing that infected animals develop immunity that protects them from re-infection by the virus.
A study with 240 covid-19 patients in New York indicates that the levels of virus-specific antibodies generated are higher in patients with severe symptoms. However, a study with hospital staff in France shows that even those with mild symptoms of the disease develop neutralizing antibodies.
Storm over chloroquine:
The Lancet published an analysis with 96,000 hospitalized patients that received hycroxycholorquine or chloroquine and concludes that the drugs do not confer a benefit and can even lead to increased frequency of heart arrhythmias. Scientists have questioned the origin of the data used for the study, although they stress that there is no evidence that chloroquine is a safe or effective treatment for Covid-19.
As a cautionary measure, the WHO has decided to suspend temporarily its trials of hydroxychloroquine as COVID-19 treatment.
China’s CanSino Biologics published the first phase 1 results for its adenoviral-vectored vaccine against Covid-19. The vaccine, tested in 108 volunteers in Wuhan, induced virus-specific antibodies and was well tolerated. A phase 2 study with the vaccine is already underway. There are some concerns that pre-existing immunity to adenovirus may lead to less robust vaccine responses.
Another vaccine based on an adenoviral vector (a chimpanzee adenovirus) developed by the Oxford vaccine group will be tested in over 10,000 people in Britain. Meanwhile, Astra Zeneca announced it will start to produce several million doses of the vaccine, with the support of a US government agency. It should be stressed that the efficacy and safety of the vaccine remain to be confirmed in larger studies.
A series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein were evaluated in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans.
Innovio’s synthetic DNA-based vaccine candidate (INO-4800) was shown to induce T cell responses and neutralizing antibodies in mice and guinea pigs.
Indirect impacts of the pandemic
The coronavirus crisis has had an indirect impact on gender equity in science. A study in Australia shows that female staff have lost more jobs and career opportunities than their male colleagues. Also, an early analysis shows that during the pandemic, women are publishing less and starting less research projects than men.
GAVI, WHO and UNICEF warn that at least 80 million infants are at risk of diseases such as diphtheria, measles, and polio as the pandemic disrupts routine vaccination efforts.
Spreading in clusters
Most SARS-CoV-2 infections are due to a few “super-spreading” events, particularly mass gatherings in closed spaces, according to the opinion of several scientists. They estimate that 10% of those infected could be responsible for 80% of secondary cases and that most transmission occurs in closed spaces.
Indirect protection by other coronaviruses?
T cells from some individuals not exposed to SARS-CoV-2 can nevertheless recognize the S protein of the virus, which suggests there could be certain cross-reactivity with the common cold coronaviruses. The authors of the study suggest that this could explain why some people develop very mild symptoms or no symptoms at all.
A Swiss team found antibodies that can neutralize SARS-CoV-2 in an individual infected with SARS in 2003. The team describes an antibody cocktail that could be used as prophylaxis or therapy to limit or treat severe disease. In contrast, two other studies with anti-SARS antibodies conclude that cross-neutralisation of SARS-CoV-2 may be rare. The good news is that one of the studies found anti-SARS antibodies in people infected 17 years ago.
Promising but preliminary results for three vaccines
One single dose of the ChAdOx1 nCoV-19 vaccine, developed by the Jenner Institute in Oxford, progected macaques against covid-19. No vaccinated animal developed pneumonia or adverse effects associated with the immune response. Last month the group launched a phase 1 clinical trial to test the vaccine’s safety. More than 1000 volunteers have participated to date.
A DNA vaccine also proved to be effective in protecting macaques against covid-19. The vaccine expressing the full-length S viral protein elicited neutralizing antibodies at a similar level to that observed in convalescent patients.
The US-based Moderna company announced the first results obtained with 8 healthy volunteers who received two doses of their mRNA vaccine. The volunteers who received the low or intermediate doses tested developed neutralizing antibodies to the virus at levels similar to people who had recovered from infection, and without adverse effects. However, these results were obtained with only 8 individuals and no details on the data were provided.
For more information on the different approaches to a coronavirus vaccine, click here.
Cats and dogs
There is evidence that infected humans can transmit the SARS-CoV-2 virus to cats, and a study shows that cats can infect each other. It is not known whether cats can infect humans. Dogs can also get infected, according to a new study.
A temporary upside
An indirect effect of this crisis has been the stark reduction in air pollution as a result of the lockdowns. In China, a study estimates that this may have averted 8,900 deaths caused by NO2 and 3,214 deaths caused by PM2.5 particles, although the scientific community underlines that the main health effects of air pollution are long-term and that the decrease in air pollution levels should be sustained over time in order to have a real impact.
Furthermore, daily global CO2 emissions decreased by 17% by early April, compared with 2019 levels. This could mean a reduction of 4 - 7% for total annual emissions in 2020, depending on the duration of the restrictions.
Further evidence on the bat-pangolin-human jump
An analysis with samples from over 220 bats collected in Yunnan province in China has identified a virus that shares 93.3% of its genome with SARS-CoV-2. It is the closest relative of SARS-CoV-2 reported to date. However, the region that binds to the human receptor only shares 61.3% of homology, suggesting that the bat virus (called RmYNo2) cannot infect humans.
In fact, another study with Malayan pangolins found that these animals host a virus related to SARS-CoV-2 and have antibodies that recognise its viral S protein. These findings support the hypothesis that SARS-CoV-2 originated from a bat virus that recombined with a pangolin virus.
Massive screening in Wuhan
After a cluster of new local cases in Wuhan city, the authorities announced that they will test its 11 million of inhabitants by PCR over the next 10 days.
A study estimates that up to 75% of passengers on the Diamond Princess cruise ship were asymptomatic, highlighting the importance of detecting all cases (symptomatic or not) as we exit the lockdown.
The analysis of semen from 38 male adults with COVID-19 detected viral RNA in 6 of the samples. This is not surprising since the receptor for viral entry (ACE2) is expressed in testis, and is not synonym of viable virus or sexual transmission.
Probably not fecal
A study shows that SARS-CoV-2 can efficiently infect and replicate in small intestine cells (enterocytes) that express the ACE2 receptor, which would explain diarrhea symptoms in many patients. Importantly, the study also shows that the virus is inactivated by colon fluids and no viable virus was recovered from stool samples of COVID-19 patients, suggesting that SARS-CoV-2 does not spread via fecal-oral transmission.
Still far from herd immunity
Around 5% of the Spanish population has antibodies against the coronavirus, according to the country’s first seroprevalence results with almost 70,000 participants. This is still far from the 50-60% immunity threshold required to stop viral spread. However, there were considerable geographical variations: from 14.3% in Soria and 11.3% in Madrid to 2% in Murcia or Asturias. These results are in line with those reported by other European countries, for example France, where the national prevalence was estimated at 4.4%. In Geneva, Switzerland, under 10% of the population had antibodies. One exception is the German town of Gangelt, where carnival festivities resulted in 15.5% of the population infected (and an infection lethality rate of 0.4%).
The Spanish results also indicate that, for every confirmed case, there were 10 undiagnosed cases, and that the average lethality in the country was around 1% (one death for every 100 people infected).
The analysis of 11,590 COVID-19 patients reveals that smoking or having smoked double the risk of disease progression.
Black men are 4.2 times more likely to die from coronavirus than their white counterparts, according to data from the UK Office of National Statistics. Differences were also observed wit other ethnic groups, such as Pakistani or Bangladeshi males. This disproportionate impact is partly due to differences in wealth, health, education and living conditions. Another study performed in California, USA, also reveals a disproportionate impact on the virus on Latin and Hispanic communities.
The combination of interferon beta-1, lopinavir-ritonavir and ribavirin in adults with moderate COVID-19 disease has given encouraging results in a controlled clinical trial performed in 6 Hong Kong hospital. The combination group had a shorter recovery time (7 days) as compared to the control group (12 days). No patient in the study died.
A team in the Netherlands and another one in Israel have identified or developed human antibodies capable of neutralizing the virus in the laboratory. Antibody-based treatments are promising but their safety and efficacy still needs to be tested in patients.
A Belgian team on the other hand has used llamas to develop antibodies that can neutralise the SARS-CoV-2 virus. These camelid antibodies have the advantage of being smaller and can therefore penetrate tissues more easily.
Mice for fighting the virus
A research team has developed mice that can be infected by the coronavirus, thanks to the expression of the human ACE2 receptor. The virus could replicate in the lungs of these transgenic mice, leading to lung inflammaiton and weight loss. This model could help evaluate antiviral therapies and vaccines.
Jumping to conclusions from one mutation
Los Alamos National Laboratory researchers described the emergence of a “more transmissible strain” of SARS-CoV-2. The study, not yet peer-reviewed, detected a form of the virus that has become dominant in Europe and that is carries a mutation in the Spike viral protein. The researchers propose that the mutation increases the virus’s capacity to infect, but provide no evidence for this hypothesis. This study led to an immediate reaction by numerous experts who note that, although not impossible, there is no evidence for the moment that this or other mutations increase the transmissibility or lethality of the virus, and that they’re not convinced that different strains of the virus exist.
The virus may have disembarked in France before 2020
Through a retrospective analysis of samples, a French group identified an individual hospitalized on December 27, 2019 and positive for SARS-CoV-2 by PCR. This suggests that the virus started circulating in France even before than believed. The patient had not travelled outside of France but his wife worked in a supermarket next to the Charles de Gaulle airport and could have been in contact with infected travellers.
The virus also replicates in the gut
Studies with human intestinal organoids and colon organoids show that SARS-CoV-2 efficiently infects and replicates cells in these organs that express the ACE2 receptor (the entry door for the virus). This could help explain the inflammatory response associated with the disease.
More on antibodies and immunity
Seroprevalence in healthcare workers: The first seroprevalence study in healthcare workers reveals that 11.2% of the staff at the Hospital Clínic in Barcelona has been infected by SARS-CoV-2. This number is lower than expected, considering it is a high-risk group. Another important finding: 39% of the workers that developed antibodies had not been diagnosed at the time of infection.
Antibodies in convalescent donors: A study led by the Mount Sinai Hospital in New York performed antibody and PCR tests on 1343 people recovered from COVID-19 and that offered to donate their plasma. There were two donor groups: those cases confirmed by PCR and those with suspected infection (not confirmed by PCR). Most had developed mild symptoms. Among the confirmed cases, 99.5% had developed virus-specific antibodies and the test used to detect them suggests that these antibodies are protective. In contrast, only 38% of suspected cases had antibodies, suggesting that many people who think had COVID-19 did not have it.
An inappropriate immune response: Experiments performed with cells, animals and analysis in patients confirm that COVID-19 is characterised by a unique and inappropriate inflammatory response defined by a low production of type I and III interferons by our first line of defence (the innate immune response) followed by an excessive production of inflammatory mediators (particularly of interleukin 6).
More on symptoms and risk factors
Doctors in Europe and the United States have reported an increase in paediatric cases (particularly in children under four years of age) with an inflammatory syndrome similar to Kawasaki disease, which could be related with coronavirus infection. The scientific community remains vigilant in monitoring these rare cases.
A third of patients hospitalised with COVID-19 in the UK died, according to a study which analysed the outcomes of 16,749 patients. The study (the largest detailed description in Europe to date) confirms that being obese, male, or elderly increases the risk of death.
Anticoagulants: Evidence for blood clotting problems in COVID-19 patients is accumulating. A study in Mount Sinai Hospital in New York analysed data from over 2,700 patients. For critical patients who were on ventilators, 63% of those given anticoagulants survived versus 29% who did not get anticoagulants. However, these results need to be confirmed with controlled clinical studies.
Further estimates of infection prevalence and mortality
The global death toll by coronavirus could be 60% higher than reported, according to an analysis of mortality statistics in 14 of the most hard-hit countries. There have been 122,000 excess deaths as compared to the same period last year. Overall deaths rose 60%in Belgium, 51%in Spain, 42% in the Netherlands and 34% in France during the pandemic compared with the same period in previous years.
In a similar exercise, a comparison of daily deaths in Italy since January 2020 with those during the same period over the previous five years concludes that the true number of COVID-19 deaths in Italy is around 50,000, more than twice the official figure, and that the fatality rate in that country was 0.8 for every 100 infected people. Extrapolating these data, the team estimated that about one-quarter of New York city's population has been infected. These estimates coincide with the first seroprevalence studies performed in the state:
Indeed, the State of New York announced the results of its first serological study with a total of 3000 people randomly tested for coronavirus antibodies in their blood. Almost 14% of them tested positive (21% in New York City). This means around 2.6 million people statewide and 1.7 million in the city were infected, way above the 263,460 declared cases across New York state. This would also mean that the real fatality rate for COVID-19 in New York was 0.5%.
More on transmission
The analysis of 391 cases and 1286 close contacts in Shenzen, China, provides further information on virus transmission. To start with, men and women are equally infected but men have a 2.5-fold risk of developing severe symptoms. Children seem as likely as adults to be infected but are less likely to develop severe disease. Along this line, a German team observed no differences in viral loads in patients from different age categories, including children. This suggests that children are as infectious as adults.
The Shenzen study also indicates that 20% of case contacts had not developed symptoms at the time of diagnosis, suggesting that there is a significant proportion of “silent carriers”.
A study in two Wuhan hospitals detected low levels of aerosols with viral RNA in isolation wards and patient rooms and higher levels in toilet areas. The results indicate that adequate ventilation, open spaces and proper disinfection of toilet areas can effectively limit the concentration of SARS-CoV-2 in aerosols.
No evidence for reinfection
Experts in South Korea announced that an analysis in patients that had tested positive by PCR days or weeks after their recovery showed that this was not due to reinfection or reactivation of the virus but to the detection of non-viable fragments of the virus. Indeed, the PCR technique does not distinguish viable virus from non-viable RNA fragments.
Treatment: more buzz on remdesivir
A clinical trial in China with 237 COVID-19 patients showed no clinical benefit por patients treated with remdesivir, although it observed a slight reduction in time to clinical recovery for patients treated earlier.
In contrast, the first results of an international multicentre trial with 1,063 patients, in which two Spanish centres participated, indicate that the time of recovery is 31% shorter for remdesivir-treated patients (average of 11 days) than for those treated with placebo (average of 15 days).
New candidates in the race for a vaccine
A Chinese team developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and macaques. Importantly, it is the first vaccine reported to protect non-human primates.
The United Kingdom also announced that a vaccine developed by the University of Oxford protects macaques from viral infection, and that it was launching the first clinical trials to assess its safety and efficacy in humans. The ChAdOx1 vaccine consists of a viral vector (the chimpanzee adenovirus) that expresses a SARS-CoV-2 protein. The Serum Institute in India announced that it has the capacity to produce millions of doses of the vaccine.
The Oxford vaccine is the third vaccine candidate funded by CEPI to entre phase 1 clinical trials, along with Inovio’s DNA vaccine (INO-4800) and Moderna’s mRNA-1273 vaccine.
A graphic guide published this week in Nature provides a good overview of the different candidate vaccines against coronavirus.
A faster, reliable test to detect the virus
A San Francisco-based team has developed a diagnostic test based on the gene-editing CRISPR-Cas12 gene-editing system. The DECTECTR assay is as sensitive and specific as the gold-standard PCR but provides a visual and faster (30-40 minutes) alternative.
The value of wastewater
An analysis of raw wastewater samples in the Parisian region over the last month detected a rise and fall in coronavirus concentrations that mirrors the shape of the epidemic curve in the region. This shows that the technique can detect sharp rises in viral RNA concentrations in wastewater before cases explode in the clinic. It can also help to assess the level of community transmission. In this sense, a first study of viral RNA in wastewater treatment plants in Brisbane, Australia, suggests that 0.1% of population in the catchment area was infected. This would mean that there were up to 7 undetected cases for every 10 detected.
Asymptomatic infections: more frequent than thought
As testing is upscaled, new data on the percentage of infected but asymptomatic individuals is emerging. In the Italian town of Vo where over 70% of its population was tested, 43% of confirmed infections were asymptomatic. Testing of the entire crew (43,000 marines) of the US carrier Theodore Roosevelt revealed that of the 600 members that tested positive, 60% had not shown symptoms. A hospital in New York city systematically screened 210 women admitted for delivery between ends of March and beginnings of April – 29 of the 33 patients who were positive for SARS-CoV-2 at admission had no symptoms.
An analysis of 94 patients shows that the highest viral load in throat swabs is seen at the time of symptom onset, which suggests that infectiousness peaks on or before symptom onset. The authors estimated that 44% of secondary cases were infected during the presymptomatic stage.
Beyond the lungs
Cardiovascular complications are emerging as a major threat in COVID-19, in addition to respiratory disease. This could be explained by recent evidence that the virus can directly infect endothelial cells (that line the blood vessels) and cause endothelial inflammation. Furthermore, doctors are seeing blood clotting among severe COVID-19 patients and are suggesting the administration of blood thinners to these patients.
A Science story reviews what we know on how the coronavirus infects and damages lungs and other tissues, particularly the heart.
To ventilate or not?
Physicians are starting to question the widespread use of ventilators for Covid-19 patients, saying that large numbers of patients could instead be treated with less intensive respiratory support.
More good news for remdesivir: Preliminary results of a clinical trial on 125 Covid-19 patients (113 of them with severe disease) indicate rapid recoveries and most patients discharged in less than a week.
More discouraging news for chloroquine: An analysis with 368 male veterans in Virginia’s Veteran Hospital found no evidence that use of hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. Furthermore, an association of increased overall mortality was identified in patients treated with hydroxychloroquine alone.
More vaccines start safety testing in human volunteers
The US company Inovio Pharmaceuticals launched a phase I clinical trial of INO-4800, its DNA vaccine for COVID-19. China’s Shenzhen Geno-Immune Medical Institute (SGIMI) has begun phase I trials of LV-SMENP-DC, a cellular vaccine made up of dendritic cells (DCs) expressing several SARS-CoV-2 proteins. Pfizer announced a joint effort with Germany’s BioNTechSE to bring its COVID-19 mRNA vaccine into phase I trials by the end of April. Phase 1 clinical trials are performed on healthy volunteers to test safety.
Measuring community transmission
Valuable insights from Iceland
Iceland has screened 6% of its total population for SARS-CoV-2 in the “deCODE” study. The first published results indicate that 13% of high-risk people (symptomatic patients, case contacts and returning travellers) were infected, versus 0.6% to 0.8% of the general population. The majority of infected people (93%) in the high-risk group developed symptoms, while almost half of infected people (43%) in the general population were asymptomatic. Women and children had a lower incidence of infection than adolescents, adults or males.
Looking back in China
A retrospective analysis of throat swabs from patients in Wuhan with influenza-like illness in January of this year found that some of the patients were positive for SARS-CoV-2, suggesting that there was community transmission of the virus in Wuhan in early January.
... and in San Francisco
Another study searched retrospectively for the virus in pooled nose and throat lavage samples collected from patients during January and February in the San Francisco Bay Area. Only two from among more than 2800 samples were positive, indicating that virus circulation in that area was very low at the early stages of the pandemic.
A global study to measure antibodies
In an effort to understand how many people have been infected with the new coronavirus, WHO is coordinating a study, Solidarity II, to test blood samples for the presence of virus-specific antibodies. Participating countries will be able to pool findings from their antibody studies to fill out the global picture. Studies include those by Stanford University, which will test 5000 people in Santa Clara county for antibodies, and the University of Bonn, which is testing 1000 people in the Heinsberg region.
Social distancing until 2022?
A modelling study suggests that social (or physical) distancing could extend, at least intermittently, into 2022 to prevent the overwhelming of hospitals. The analysis predicted SARS-CoV-2 transmission during the next five years, taking into account yet-unknown variables such as the seasonality of the virus, the duration of immunity, and the cross-protection – or not – arising from immunity to the coronaviruses that cause common colds. If immunity to SARS-CoV-2 is transient, regular circulation and annual wintertime waves are expected. If immunity lasts longer, the time between surges of cases could be two to three years or longer. The authors conclude that serological studies over time are vital to determine the extent and duration of immunity to the virus.
An analysis of COVID-19 patients in a New York City hospital suggests that obesity increases the risk of hospitalisation and need for critical care. This has important implications in a country where nearly 40% of adults are obese (body mass index equal to or greater than 30).
An “early snapshot” of COVID-19 cases in NYC confirms trends observed in other countries: older people were more likely to be hospitalised, and men were more likely to develop severe disease. In addition, black American men are dying in much higher numbers. Reasons for this likely include higher risk of exposure to the virus, higher prevalence of risk factors such as obesity and diabetes, and less access to health care.
Mini-organs to study infection
To understand how COVID-19 enters the body and does its damage, a Canadian team is developing "organs-on-a-chip" (minuscule models of the nose, mouth, eyes and lungs). This will allow them to study how the virus evades the body’s first line of defense (the innate immune response).
Antiviral drugs: The use of remdesivir in 53 patients (22 in the United States, 22 in Europe or Canada, 7 in Japan) has yielded promising, although preliminary, results: clinical improvement was observed in 36 of 53 patients (68%). A laboratory study has identified a unifying and detailed mechanism by which remdesivir inhibits RNA synthesis in coronaviruses.
Chloroquine: A trial in Manaus testing chloroquine for the treatment of COVID-19 patients needed to be stopped due to cardiac complications in patients treated with high doses of the drug. Sweden has also recommended not using the drug outside of clinical trials due to “a serious effect on the heart” linked to using the medication.
On the Origins of the Virus
A genetic analysis of 68 coronaviruses estimates that the ancestor of SARS-CoV-2 split 40 to 70 years ago from RaTG13, a closely related virus that infects bats but not humans.
What is the Real Number of Infected People?
This remains one of the biggest unknowns in this pandemic. A team at the University of Goettingen estimates that, in average, the countries have only detected 6% of the coronavirus infections, and that the real number of infected people worldwide could be several tens of millions. Germany may have detected around 15% of its cases, while Spain only 1.7%. South Korea may have detected almost half of its infections.
A research team will analyse wastewater for the virus’ genetic material as a way to estimate the total number of SARS-CoV-2 infections in a community. Wastewater testing could also be used as a surveillance strategy that provides early warning if the virus returns to a community.
Masks or not masks?
The widespread use of masks remains a matter of debate. A research team reviewed 31 studies and concluded that there is not sufficient evidence to support the widespread use of masks, although there is enough to support their use by vulnerable people when in temporary risk situations (shared public spaces, transport, etc.). On the other hand, a research team found that masks reduced the amount of coronavirus RNA in both coarse droplets and finer ‘aerosol’ droplets. It is possible that, given the uncertainty, the precautionary principle will be prevail.
Air pollution and COVID-19 lethality
An analysis performed by a Harvard University team suggests that people living in areas with higher air pollution levels are more likely to die from COVID-19 than those living in cleaner areas. The research indicates that even a small increase in fine particle levels is associated with a 15% increase in the death rate. Another Italian study also notes that the high fatality rates observed in the north of the country correlate with the highest levels of air pollution.
In this sense, data from China already suggested that smokers seemed to be more susceptible to severe forms of disease
Treatment: modulate the inflammatory storm in critically ill patients
An “inflammatory cytokine storm” seems to be frequent in patients with severe COVID-19 disease. This has opened the door to testing drugs that can modulate this phenomenon. Interleukin 6 is a cytokine that seems to be particularly increased in critically ill patients, according to a study. Several teams, including a French team and a Chinese one, have used antibodies against IL6 (tocilizumab) to treat patients with severe disease, with promising results.
Animal models to study the disease
A German team confirms that pigs and chicken are not susceptible to SARS-CoV-2 infection but that the virus replicates efficiently in ferrets. In fact, ferrets reproduce many of the clinical symptoms of the human infection (although they do not die), making them a good animal model for COVID-19.
Loss of Smell and Taste: First Signs?
Almost 60% of patients who were subsequently confirmed as positive for SARS-CoV-2 infection reported losing their sense of smell and taste, compared with 18% of those who tested negative, according to data collected via a symptom tracker app developed by British scientists. These results confirm previous reports indicating that the loss of sense of smell and taste are frequent and could be the first signs of disease.
Adjusting the Fatality Estimates
A study estimates that the adjusted case fatality rate in China was 1.4% for confirmed cases (a figure that increases to 6.4% for those over the age of 60 and to 13.4% for those over the age of 80). If the infected but undiagnosed cases are also considered, the adjusted infection fatality rate (IFR) was 0.66%. The average time between symptom onset and death was 17.8 days, and 24.7 days between symptom onset and hospital discharge.
Confinement Measures Work
Using a series of mathematical models, the Imperial College of London estimates that, with the measures implemented in 11 European countries (including Spain) until the end of March, some 59,000 deaths were averted. It also estimates that between 7 and 43 million people have been infected with the virus (through March 28), which represents between 1.9% and 11.4% of the total population of Europe. (In Spain it could be even higher – 15% of the population).
Moreover, a study in Science estimates that the Wuhan travel ban, combined with the Chinese national response, limited the number of confirmed COVID-19 cases to 96% fewer than what would otherwise be expected after 50 days.
Another Vaccine in Phase 1
The Jenner Institute and Oxford Vaccine announced they are starting to recruit volunteers to test the safety of their COVID-19 vaccine. The vaccine consists of a modified chimpanzee adenovirus that expresses viral Spike proteins.
An Old Vaccine to Boost the Immune System
Germany will start to test the efficacy of a modified version of the BCG vaccine against tuberculosis to learn whether it protects healthcare workers and the elderly against COVID-19. Other countries have also started to test this vaccine (see last week’s update). There is evidence that the BCG vaccine, developed a century ago, may boost immune responses against several respiratory viruses.
A Chinese team isolated different coronaviruses from Malayan pangolins (Manis javanica) illegaly traded in southern China. It identified two sublineages highly related to SARS-CoV-2, one of which had a very similar sequence in the domain that allows the virus to enter the cell. This suggests that pangolins could be intermediary hosts for new coronaviruses, and should be removed from wet markets.
Another study indicates that SARS-CoV-2 cannot replicate in dogs, pigs, chickens or ducks, but can do so in cats and ferrets. However, this does not mean that domestic cats or ferrets are a source of viral transmission.
Symptoms, clinical evolution and fatality rate: latest data
Regarding the percentage of asymptomatic cases, a couple of recent studies estimate it ranges between 17 and 30%. However, large-scale serological studies will be needed to assess the real percentage of infected but asymptomatic people.
According to the latest update by the ECDC, which analysed 43,438 cases from 17 European countries, 30% of these cases were hospitalized and 4% of cases required intensive care or respiratory support.
A marker for predicting risk?
A study that analysed viral load (i.e. the amount of virus present in the sample) among 76 patients with moderate to severe symptoms provides two important insights. The first is that the viral load reaches its peak when the symptoms first appear, confirming that the days right before and after symptom onset are when the patient is most contagious. The second is that the most severe cases had a much higher viral load than the moderate cases. This means that viral load at the beginning of the disease may be a good marker of prognosis.
One global assay, four treatments
The WHO announced a large global trial, called SOLIDARITY to test what it considers to be the most promising therapies: remdesivir (an antiviral drug originally tested for Ebola); chloroquine and hydroxychloroquine (an old antimalaria drug); lopinavir and ritonavir (an HIV therapy); and that same combination plus interferon beta (a molecule with antiviral properties). The trial will include many thousands of patients in dozens of countries.
According to Nature, hospitals in New York are getting ready to test blood from recovred patients to treat the disease. The idea of using “convalescent plasma” is not new- it has been tested in other diseases including Ebola with rather inconclusive results. Several hospitals will participate in assays to test its efficacy in treating the disease (both for severe cases and at the onset of disease) or even in preventing it (among healthcare workers).
In addition, Vir Biotechnology has announced that two of its laboratory-produced antibodies can neutralise the SARS-coV-2 virus, and they will start testing them in people in the next three months.
An old vaccine
Research teams in Australia, Greece and the Netherlands will start a clinical assay to test whether the tuberculosis vaccine can enhance the immune response to SARS-CoV-2 and avoid or attenuate the disease. There is some evidence that the vaccine, developed 100 years ago and with limited efficacy for tuberculosis, may boost the immune response against viruses.
Transmission: who, when and how
One of the most pressing questions in this epidemic is understanding who can transmit the virus and during what duration of time.
Concerning the who, several studies confirm that infected people who have not yet developed symptoms contribute substantially to viral transmission. (A study based on data from China estimates that up to 80% of cases were fuelled by pre-symptomatic transmission, while another study estimated it to be 48% in Singapore and 62% in Tianjin, China.)
The time-period during which someone is infectious is still controversial. It seems as if people can be contagious starting one or two days before symptom onset (most people develop symptoms five to seven days after infection) and during at least ten days after developing symptoms. In a study of German patients, virus-specific antibodies were detected six to ten days after symptom onset and this coincided with a steady decrease in viral load in respiratory airways and hence with a decrease in the capacity to infect.
Concerning the how, infectious virus was found in throat and lung samples but not in blood, urine or faeces of these patients.
Importantly, both the analysis of thousands of cases in China and experiments performed with macaques in the laboratory indicate that a patient who has recovered from COVID-19 cannot get re-infected, meaning that protective immunity is generated. How long this immunity will last is still an open question.
The real number of infected people: one of the big unknowns
One new study estimates that for every confirmed COVID-19 case, there are five to ten cases without symptoms or with mild symptoms that go undetected. This large amount of uncertainty explains why the case fatality rate (i.e. how many people die out of 100 infected people) continues to be one of the big unknowns for this new virus, despite the fact that such a figure is vital for better predicting the impact of the epidemic and guiding the public health response. According to an analysis with data from different countries, the range for the case fatality rate may be between 0.3% and 3%, but it will be necessary to perform serological studies (seeking for antibodies against the virus) at the population level in order to have a better idea of the size of the infected population and the real case fatality rate.
South Korea, with its approach based on massive screening, has not only managed to contain the epidemic through the identification and isolation of cases and contacts, but has also provided more reliable numbers than other countries for estimating the dynamics of transmission and the fatality rate of the virus.
The virus does not affect everyone in the same way
What is clear, both in China and other countries such as Italy, is that the virus is not an “‘equal opportunity”’ killer. The fatality rate drastically increases with age –from 0% in those under 30 years of age, to 1% in 50-59 year-olds, and up to almost 20% in people over 80 (according to the latest data from Italy). The virus also disproportionately affects those with underlying chronic conditions, particularly hypertension and diabetes. In China, patients with hypertension accounted for up to 23% of severe cases and up to 40% of deaths. It is thought that this could be related to hypertension drugs inhibiting the angiotensin- converting enzyme, which leads to an overexpression of the receptor ACE2, which is the “entry door” that the virus uses to infect the cell.
Interestingly, children do seem to get infected, but —fortunately— they rarely develop severe symptoms. The reasons for this are still unknown, nor is it known what role children play in the transmission of the virus.
Treatment: repurposing existing drugs
There is no specific treatment for this new virus. However, the efficacy of other antiviral drugs onin the market is currently being tested.
One of the most promising candidates is remdesivir, due to its broad antiviral activity and encouraging results obtained in animal models. It was first used on a COVID-19 patient in the US (successfully) and is currently being tested in clinical assays in several countries, including Spain (with the participation of ISGlobal and Hospital Clinic).
Another candidate is the liponavir/ritonavir combination (used to treatfor HIV), but an initial trial did not yield positive results.
Vaccine: work in progress
The US-based company Moderna announced the Phase I clinical trial to test its mRNA-based vaccine for SARS-CoV-2. This innovative approach, which relies on instructing the own body to synthesize viral proteins, could be more effective and easier to scale up than other vaccines, but its safety has not yet been tested. The German company Curevac is also developing an mRNA-based vaccine but has not started clinical trials. Both candidate vaccines have received funding from CEPI, an international coalition to develop innovative vaccines.
The Chinese authorities recently announced they will start clinical trials with a subunit vaccine. This strategy is already used in a number of existing vaccines (Hepatitis B, diphtheria, HPV, etc) and is very safe. However, the immune responses generated by these vaccines are not as effective or long-lasting.
In any case, the safety and efficacy of all vaccine candidates must first be tested at a small scale before they can be used on the wider population. In the best of cases, we will have a vaccine in 12 to 18 months.