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From immunity to the role of genetics, the prestigious scientific journal Nature examines five pressing questions about COVID-19 that researchers are addressing.

UNITED STATES (Reuters) To mark six months since the world first learned of the disease responsible for the pandemic, Nature looks at some of the key questions researchers have yet to answer.

In late December 2019, reports emerged of mysterious pneumonia in Wuhan, China, a city of 11 million people in the southeastern province of Hubei. The cause, Chinese scientists, quickly determined, was a new coronavirus distantly related to the SARS virus that had emerged in China in 2003, before spreading globally and killing nearly 800 people.

Six months and more than 10 million confirmed cases later, the VID-19 pandemic has become the worst public health crisis in a century. More than 500,000 people have died worldwide. It has also catalyzed a revolution in research, as scientists, physicians, and other academics have worked at breakneck speed to understand COVID-19 and the virus that causes it: SARS-CoV-2.

They have learned how the virus enters and hijacks cells, how some people fight it, and how it eventually kills others. They have identified drugs that benefit the sickest patients, and many more potential treatments are being developed. They have developed nearly 200 potential vaccines, the first of which could be proven effective by the end of the year.

But for every idea of COVID-19, more questions arise, and others persist. This is how science works. To commemorate six months since the world first learned of the disease responsible for the pandemic, the science journal Nature looks at some of the key questions that researchers do not yet have answers to.

1. Why do people respond so differently?Some people never develop symptoms, while others, some apparently healthy, have severe or even fatal pneumonia.

One of the most striking aspects of COVID-19 is the marked differences in the experiences of the disease. Some people never develop symptoms, while others, some apparently healthy, have severe or even fatal pneumonia. The differences in clinical outcome are dramatic, says Kri Stefnsson, a geneticist and CEO of DeCODE Genetics in Reykjavik, whose team is looking for human gene variants that may explain some of these differences.

That search has been hampered by the relatively small number of cases in Iceland. But last month, an international team that analyzed the genomes of approximately 4,000 people in Italy and Spain discovered the first strong genetic links to severe COVID-19. People who developed respiratory failure were more likely to carry one of two particular genetic variants than people without the disease.

One variant lies in the region of the genome that determines the ABO blood type. The other is close to several genes, including one that encodes a protein that interacts with the receptor the virus uses to enter human cells, and two others that encode molecules linked to the immune response against pathogens. The researchers are part of the COVID-19 Host Genetics Initiative, a global consortium of groups that are pooling data to validate the findings and discover more genetic links.

The variants identified so far appear to play a modest role in the outcome of the disease. A team led by Jean-Laurent Casanova, an immunologist at Rockefeller University in New York City, is looking for mutations that will play a larger role. His team is combining the entire genomes of otherwise healthy people under 50 who have experienced severe cases of COVID-19, he says, such as the guy who ran a marathon in October and now, five months later, is in the ICU, intubated and ventilated. Extreme susceptibility to other infections, such as tuberculosis and Epstein-Barr virus, a generally harmless pathogen that sometimes causes serious illness, has been attributed to mutations in individual genes. Casanova suspects that the same will be true for some cases of COVID-19.

2. What is the nature of immunity, and how long does it last?Researchers do not yet know what level of neutralizing antibodies is needed to fight SARS-CoV-2 reinfection or reduce the symptoms of COVID-19 in a second illness.

Immunologists are working feverishly to determine what immunity to SARS-CoV-2 might look like and how long it might last. Much of the effort has focused on neutralizing antibodies, which bind to viral proteins and directly prevent infection. Studies have found that levels of neutralizing antibodies to SARS-CoV-2 remain high for a few weeks after infection and begin to decline.

However, these antibodies may remain at high levels longer in people who had particularly severe infections. The more virus, the more antibodies and the longer they last, says immunologist George Kassiotis of the Francis Crick Institute in London. Similar patterns have been seen with other viral infections, including SARS (severe acute respiratory syndrome). Most people with SARS lost their neutralizing antibodies after the first few years. But those who had it severely still had antibodies when they were re-tested 12 years later.

Researchers do not yet know what level of neutralizing antibodies is needed to fight SARS-CoV-2 reinfection, or at least to reduce the symptoms of SARS-CoV-19 in a second illness. And other antibodies may be essential for immunity. Virologist Andres Finzi, of the University of Montreal in Canada, plans to study the role of antibodies that bind to infected cells and mark them for execution by immune cells, a process called antibody-dependent cellular cytotoxicity, in response to SARS-CoV-2.

Ultimately, a complete picture of immunity to SARS-CoV-2 is likely to extend beyond the antibodies. Other immune cells called T cells are essential for long-term resistance, and studies suggest that SARS-CoV-2 is also urging them to arms. People equate antibodies with immunity, but the immune system is such a wonderful machine, Finzi explains. Its much more complex than just antibodies.

Because there is not yet a clear, measurable marker in the body that correlates with long-term immunity, researchers must reconstruct the mosaic of immune responses and compare it to responses to infections with other viruses to estimate how long the protection might last. Studies of other coronaviruses suggest that sterilizing immunity, which prevents disease, may last only a few months. But protective immunity, which can prevent or alleviate symptoms, may last longer than that, warns Shane Crotty, a virologist at the La Jolla Institute of Immunology in California.

3. Has the virus developed any mutations of concern?The versions of the coronavirus identified at the beginning of outbreaks in hot spots such as Lombardy in Italy or Madrid, for example, may appear more lethal than those found in later stages or elsewhere (AFP)

All viruses mutate as they infect people, and SARS-CoV-2 is no exception. Molecular epidemiologists have used these mutations to track the global spread of the virus. But scientists are also looking for changes that affect their properties, such as making some lineages more or less virulent or transmissible. Its a new virus; if it became more severe, thats something Id like to know, says David Robertson, a virologist at the University of Glasgow, UK is cataloging mutations in SARS-CoV-2. Such mutations also have the potential to diminish vaccines effectiveness by altering the ability of antibodies and T cells to recognize the pathogen.

But most of the mutations will have no impact, and choosing the ones of concern is a challenge. Versions of the coronavirus identified at the beginning of outbreaks in hot spots such as Lombardy in Italy or Madrid, for example, may appear more lethal than those found at later stages or elsewhere. But such associations are probably spurious, says William Hanage, an epidemiologist at Harvard Universitys TH Chan School of Public Health in Boston, Massachusetts: health officials are more likely to identify severe cases in the early, uncontrolled stages of an outbreak. The widespread of specific mutations could also be due to founder effects, in which lineages that emerge early in transmission centers such as Wuhan or northern Italy have a mutation that is transmitted when outbreaks spread elsewhere.

Researchers are debating whether the widespread prevalence of a mutation in the spike protein of the virus is a product of a founder effect or an example of a consequent change in the biology of the virus.

The mutation appears to have emerged around February in Europe, where most circulating viruses now carry it and are now found in all regions of the world. Several pre-print studies have suggested that this mutation makes the SARS-CoV-2 virus more infectious to cultured cells, but it is not clear how this property translates into humans.

4. How well will a vaccine work?With governments and industry injecting billions into the development, testing, and manufacturing of vaccines, scientists say vaccines could be available in record time. It may not be fully capable.

An effective vaccine may be the only way out of the pandemic. There are currently approximately 200 in development worldwide, with about 20 in clinical trials. The first large-scale efficacy trials to determine whether any vaccine works will begin in the coming months. These studies will compare rates of infection with COVID-19 among people receiving a vaccine and those receiving a placebo.

But there are already clues in the data from animal studies and early human trials, mainly safety tests. Several teams have conducted challenge tests in which animals receiving a candidate vaccine are intentionally exposed to SARS-CoV-2 to see if it can prevent infection. Studies in macaque monkeys suggest that vaccines may do a good job of preventing lung infection and resulting pneumonia, but not blocking infection in other parts of the body, such as the nose. Monkeys that received a vaccine developed by the University of Oxford, UK, and were then exposed to the virus had viral genetic material in their noses comparable to levels in unvaccinated animals. Results like this increase the chance of a COVID-19 vaccine preventing severe disease, but not the spread of the virus.

Data in humans, although scarce, suggest that COVID-19 vaccines cause our bodies to produce potent neutralizing antibodies that can block infection of the virus by cells. It is still unclear whether the levels of these antibodies are high enough to stop new infections or how long these molecules persist in the body.

With governments and industry injecting billions into the development, testing, and manufacturing of vaccines, scientists say, a vaccine may be available in record time, but it simply may not be fully effective. We could have vaccines in the clinic that are useful in people within 12 or 18 months, Dave OConnor, a virologist at the University of Wisconsin-Madison, told Nature in May. But were going to need to improve them.

5. What is the origin of the virus?Most researchers agree that the SARS-CoV-2 coronavirus probably originated in bats, specifically horseshoe bats. This group is home to two coronaviruses closely related to SARS-CoV-2. One, called RATG13, was found in intermediate Horseshoe bats (Rhinolophus affinis) in southwestern Chinas Yunnan Province in 2013. Its genome is 96% identical to SARS-CoV-2. The next closest match is RmYN02, a coronavirus found in Malayan horseshoe bats (Rhinolophus malayanus), which shares 93% of its genetic sequence SARS-CoV-2.

A comprehensive analysis of more than 1,200 coronaviruses sampled from bats in China also points to the Horseshoe bats in Yunnan as the likely origin of the new coronavirus. But the study does not exclude the possibility that the virus originated from horseshoe bats in neighboring countries, including Myanmar, Laos, and Vietnam.

The 4% difference between the genomes of RATG13 and SARS-CoV-2 represents decades of evolution. Researchers say this suggests that the virus may have passed through an intermediate host before spreading to people, just as it is believed that the virus causes SARS to pass from horseshoe bats to civets before reaching people. Some candidates for this animal host appeared at the beginning of the outbreak, and several groups focused on pangolins.

Researchers isolated coronaviruses from Malaysian pangolins (Manis javanica) confiscated during anti-smuggling operations in southern China. These viruses share up to 92% of their genomes with the new coronavirus. Studies confirm that pangolins may harbor coronaviruses that share a common ancestor with SARS-CoV-2, but do not prove that the virus jumped from pangolins to people.

To uniquely track the virus journey to people, scientists would need to find an animal that harbors a more than 99% similar version of SARS-CoV-2, a perspective complicated by the fact that the virus has spread so widely among people that they, in turn, passed it on to other animals, such as cats, dogs, and farm minks.

Zhang Zhigang, an evolutionary microbiologist at Yunnan University in Kunming, says efforts by research groups in China to isolate the virus from livestock and wildlife, including civets, have been uncovered. Groups in Southeast Asia are also looking for the coronavirus in tissue samples from bats, pangolins, and civets.

The Yucatan TimesNewsroom

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