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 03/04/2020 and 09/04/2020]
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.
[Evidence published between 28/03/2020 and 02/04/2020]
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.
[Evidence published between 18/03/2020 and 27/03/2020]
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.
[Evidence published until 18/03/2020]
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.