Which companies are leading the coronavirus vaccine race? – Fox Business

At present, big-name pharmaceutical and biotechnology firms around the globe are in an intense race to develop the worlds first vaccine for the novel coronavirus which would potentially lead to national bragging rights and huge profits for successful companies as countries hope to put their economy back on track earlier than other nations.

A total of 142 vaccines were being developed as of Monday, of which 13 are were clinical evaluation, according to the World Health Organization. British drugmaker AstraZeneca PLC and U.S. biotech firm Moderna Inc. are considered two of the leading candidates to put the worlds first vaccine on the market as early as by the end of this year. At home, AnGes Inc., which has teamed up with Takara Bio Inc. and Osaka University, is considered the front-runner, aiming to launch the vaccine as early as next spring, followed closely by Shionogi & Co. among other domestic efforts.

But at the same time, questions arise. Is there a possibility that the safety or efficacy of the vaccine may be overlooked so as to prioritize the speed of the development? If Japan is lagging behind other countries in vaccine development, how would that affect the country when it tries to import them?

Dr. Tetsuo Nakayama, a project professor at Kitasato Institute for Life Sciences and director of the Japanese Society of Clinical Virology, spoke to The Japan Times to help shed some light on the current development of vaccines at home and abroad and the risk of the heated competition.

Which companies are leading the global race in developing the vaccine?

U.S. firm Moderna looks to be making the most progress.

It has announced its messenger RNA vaccine has generated antibodies in people in a phase one trial (designed to assess its safety and tolerance), but theres no detailed data to show that it would protect them against infection.

Simply put, an influenza shot injects a protein into the body. Messenger RNA and DNA vaccines, meanwhile, force production of proteins that resemble the pathogen, so in that sense the most we can expect may be about the same as the influenza vaccine in terms of reducing the most severe effects of the disease, and it may not have the ability to put the disease under control.

The most important thing is whether the use of DNA or messenger RNA vaccines stimulate the production of protective neutralizing antibodies and induce the cellular immune response. At this point, it remains unclear whether the DNA vaccine under development by AnGes or messenger RNA vaccine by Moderna would induce the cellular immune response.

But in a worst-case scenario, some antibodies may worsen the disease by essentially helping increase the virus inside the cell in a phenomenon called antibody dependent enhancement (ADE).

We dont know whether there are concerns for ADE at this point after (getting the vaccine and being) infected with the novel coronavirus.

There are lots of unknowns, but I dont think the vaccine would be ready by the end of the year. Osaka University has been working with Takara Bio Inc. and AnGes Inc. on a DNA vaccine similar to messenger RNA.

So is ADE a cause for concern for the general public?

If the vaccine is only to curb the occurrence of severe symptoms, the subjects for vaccination would likely be limited to older people or people with pre-existing conditions, and its too early to tell whether its a vaccine to be administered to children or adults in general.

Are there promising vaccine candidates worldwide?

There are two objectives of vaccines.

One is to prevent infection and another is aimed at not necessarily protecting against the disease but preventing severe symptoms.

Everybody is talking about developing a vaccine to halt the spread of infections, but thats not something that can typically be achieved without a live vaccine. For example, the measles vaccine is a live vaccine, curbs the infection and prevents the risk of a serious disease for people.

But influenza, like the coronavirus, causes a respiratory tract infection, so its difficult to prevent the infection via vaccination through intramuscular injection. The vaccines under development could be similar in terms of efficacy to the influenza vaccine.

The West and China are leading the vaccine development. Will there be a delay for Japan to introduce the vaccines to its own people?

Yes, I acknowledge that theres going to be a delay because those countries would prioritize the vaccinations of their own people.

I have seen no reports that the Japanese government has been providing funds to overseas manufacturers of vaccines, though the Trump administration in the U.S. has been funding various projects overseas to secure vaccinations for its citizens in case the domestic efforts fall through.

The European Union and the U.S. have the Mutual Recognition Agreement, which allows the drugs to be used within each others borders by avoiding the duplication of clinical trials.

But Japan still requires additional clinical trials, making it one of the very few jurisdictions that still requires that in the world.

During the swine influenza pandemic in 2009, Japan imported vaccines, but by the time Japan finished clinical trials on the imported vaccines, Japanese manufacturers had already supplied tens of millions of domestically produced vaccines and the epidemic was over, so the vast majority of the imported vaccines were not used in the end.

Is it possible that the same thing could happen this time around?

Its hard to say for certain. But Japan has to undergo an additional clinical trial even if it wants to import a vaccine that has cleared regulatory approval overseas. So, under current rules, theres going to be a delay.

Japan approved remdesivir for treatment of severe COVID-19 cases last month, soon after it gained approval from the U.S. Food and Drug Administration. So it will be different when Japan imports a vaccine made overseas, wont it?

That is because dozens of clinical trials on remdesivir had been conducted in Japan.

It doesnt mean that Japan does not have to go through a trial. But while were waiting for Japanese approval to be able to use the overseas vaccines, Japanese manufacturers should start producing home-made vaccines.

I have often said this, but a vaccine is a weapon to protect ones own citizens, so we should not rely on overseas manufacturers.

Because people can get re-infected with the virus, is the vaccination essential for the general public?

Its the same thing with influenza. You can contract it many times.

Because the novel coronavirus is also a respiratory tract infection, normally a vaccination would not protect against infection itself. So even if a person contracts the virus, it doesnt necessarily mean that the person doesnt get infected again.

So in a nutshell, are people supposed to take the vaccination every year, for instance?

We still dont know that for sure if thats going to be necessary if the novel coronavirus keeps changing its genetic mutations.

There are different types of the coronavirus confirmed across the globe. If a person gets vaccinated, does the person have an antibody against all types?

The person would have some degree of protection but its still too early to tell whether the vaccination would create cross-reactive antibodies in different subtypes of the virus.

With maybe too much focus globally on developing the vaccine as soon as possible, are there concerns that important issues like the vaccines efficacy, safety or side effects could be neglected?

Yes, those concerns are real, as weve seen a lot of failures in the vaccine development in the past. For example, a dengue fever vaccine made by Sanofi and based on a yellow fever vaccine embedded with the dengue virus appeared to be effective, but it caused the deaths of children who had been given the vaccination due to the phenomenon called ADE, explained earlier. There are always safety concerns, so the vaccination development must be conducted cautiously.

Are there concerns that Japanese vaccine manufacturers would turn a blind eye to certain aspects of safety, efficacy and side effects?

No. Japanese people are very sensitive and particular about adverse reactions such as fever or local reactions, so Japanese vaccines are among the best in the world and are considered extremely safe.

How long do you expect it to take for the vaccines to be available for all the general public?

I would expect as early as next year, but it would depend on the production capacity.

Texas Gov. Greg Abbott issued a separate executive order earlier Thursday to pause elective surgeries in four Texas counties: Bexar, Dallas, Harris and Travis.

DALLAS This story will be continuously updated.

Texas Gov. Greg Abbott announced Thursday the pause of further reopening phases in the state due "to the recent increase in positive COVID-19 cases and hospitalizations."

"The last thing we want to do as a state is go backwards and close down businesses," he said in a news release. "This temporary pause will help our state corral the spread until we can safely enter the next phase of opening our state for business."

Businesses can continue to operate at occupancy levels set under current phases of reopening and should observe the minimum health protocols set by state health authorities, according to the governor.

Abbott said he doesn't want to revert to earlier business closures.

The governor began reopening the state with a series of orders that started in late April and continued into early June.

Abbott continued to call on residents to do their parts in stopping the spread.

"I ask all Texans to do their part to slow the spread of COVID-19 by wearing a mask, washing their hands regularly, and socially distancing from others," Abbott said in a statement. "The more that we all follow these guidelines, the safer our state will be, and the more we can open up Texas for business.

Earlier Thursday, Abbott announced he was pausing elective surgeries in four of the state's largest counties: Bexar, Dallas, Harris, and Travis.

Tarrant County was not included in Abbott's new order.

For a daily roundup of the biggest coronavirus news from around North Texas and beyond,sign up for the WFAA COVID-19 email newsletter.

Cornyn, Cruz send letter requesting continued federal support for COVID-19 testing sites

U.S. Sens. Ted Cruz and John Cornyn sent a letter to Health and Human Services and FEMA urging continued federal support for community-based COVID-19 testing sites in Texas.

The senators sent the letter Thursday addressed to Secretary of Health and Human Services Alex Azar and Administrator of the Federal Emergency Management Agency Pete Gaynor urging them to continue the federal support for sites in Texas as testing capacity remains a crucial component to defeating COVID-19, strengthening the economy, and safely getting Texans back to work.

Dallas County reports 403 new cases, 6 additional COVID-19 deaths

In Dallas County, health officials have noted the spread of the disease among child care facilities.

More than 31 cases reported since June 1 have been linked to 18 child care centers.

Health officials reported 403 new cases Thursday and six additional deaths due to COVID-19.

Among those who died are:

Denton County reports 77 new cases, Collin County reports 37 new cases

Denton County health officials reported 77 new cases Thursday, and Collin County officials reported 37 new cases of COVID-19.

Collin County also reported one new death from the disease.

Both counties have reported nearly 2,500 coronavirus cases since tracking began in March. The counties also each report more than 1,000 people have recovered from the disease.

Tarrant County reports 517 new coronavirus cases

Tarrant County health officials reported 517 new confirmed cases of the coronavirus on Thursday.

The county has reported 10,363 COVID-19 cases since tracking began in March. In the past seven days, the county has recorded 1,804 new cases.

There are more than 4,400 actives cases of the disease in Tarrant County, according to state data.

Texas Juvenile Justice Departments says 6 youths, 17 staff positive for COVID-19

Texas Juvenile Justice Department announced five more youths at its facilities have tested positive for COVID-19 Thursday, bringing the total to seven positive cases.

The department says five juveniles at Giddings State School have been on medical quarantine since June 22, after an initial reported that one tested positive on that day.

One juvenile at Gainesville State School tested positive earlier this week.

The department also reported that 17 staff members have tested positive for COVID-19 at the following facilities:

Kay Bailey Hutchison Convention Center will not be used as overflow hospital

In a tweet Thursday afternoon, Dallas Mayor Eric Johnson said the Kay Bailey Hutchison Convention Center will not be used as an overflow hospital at this time.

Johnson said officials with Dallas County and the DFW Hospital Council told him they believe they are capable of handling COVID-19 hospitalizations with the current medical facilities available.

Gov. Greg Abbott announced in March that the convention center would serve as an overflow hospital if needed, but it has not been used during the pandemic.

Tarrant County issues mask mandate

Tarrant County officials announced Thursday they were issuing a mask order, saying business must require guests and employees to wear masks. That order goes into effect at 6 p.m. Friday.

Under the order, businesses in violation could face a $1,000 fine.

The Tarrant County announcement comes just one day after Dallas Mayor Eric Johnson led a news conference with a simple statement: "Wear a mask."

"This is the single most important thing that you can do to slow the spread of COVID-19," Johnson said, seated at Dallas City Hall, wearing a mask.

Prior to Johnson's statement, Abbott said Texas is facing a massive outbreak in the coronavirus pandemic. He says some new local restrictions may be needed to protect hospital space for new patients.

On Saturday, a new order went into effect requiring businesses and people across Dallas County to wear a face covering.

Gov. Abbott issues orders suspending elective surgeries in four Texas counties

All hospitals in Harris, Bexar, Dallas, and Travis counties are directed to postpone all surgeries & procedures that aren't immediately, medically necessary to help stop the spread of COVID-19.

The goal of the executive order is to ensure hospital bed availability for COVID-19 patients as Texas faces an increase in COVID-19 cases and hospitalizations.

On Wednesday Abbott conceded thatTexas is facing a "massive outbreak" of COVID-19.

As Texas faces a rise in COVID-19 cases, we are focused on both slowing the spread of this virus and maintaining sufficient hospital capacity for COVID-19 patients, said Governor Abbott. These four counties have experienced significant increases in people being hospitalized due to COVID-19 and todays action is a precautionary step to help ensure that the hospitals in these counties continue to have ample supply of available beds to treat COVID-19 patients."

Main St. Fort Worth canceled for 2020

The 2020 Main St. Fort Worth Arts Festival has been canceled, event organizers say.

The event, which was originally scheduled to take place April 16 to 19, had been rescheduled to September.

The decision to call off this year's event was made by the board of directors of Downtown Fort Worth Initiatives, Inc. and the event organizers.

"Cancellation is due to increasing Coronavirus (COVID-19) concerns and governmental recommendations for restricting large gatherings in order to prevent community spread," a release posted online read.

Event organizers said while the decision was difficult, the safety and well-being of everyone involved remains their top priority.

People are encouraged to support artists by visiting the online gallery.

Dallas Zoo to require face coverings for guests ages 10 and older

The Dallas Zoo announced Thursday that it would be updating its policy on face masks.

Beginning immediately, visitors ages 10 years and older would be required to wear a face mask. The zoo also said it strongly encouraged children under 10 years of age to wear masks as well.

Guests who do not comply will be asked to leave, according to zoo officials.

Guests can take off their masks while eating or drinking, if they have a health reason that prevents wearing one, or take a short break from wearing masks while outdoors, according to a release from the zoo.

5 Kaufman County courthouse employees test positive for COVID-19

Five Kaufman County courthouse employees have tested positive for COVID-19 in the last week, Judge Hal Richards announced Thursday.

According to the courthouse, two employees tested positive last week and three tested positive this week.

Judge Richards said those who were in direct contact with the employees have been contacted and are encouraged to be tested.

Everyone who enters the Kaufman County courthouse is offered a mask, and those who enter are also urged to maintain six-foot social distancing.

Richards said additional cleaning of the courthouse has been completed following the positive test results. Anyone who has questions concerning COVID response efforts at the courthouse are asked to contact their department head or Richards office.

More on WFAA:

While many Americans still debate whether or not to wear face masks, a new study found that face mask use has prevented thousands coronavirus cases. The study, published in the journal Health Affairs, estimates between 230,000 and 450,000 COVID-19 cases were prevented in states that required face masks between April 8 and May 15. Researchers said wearing face masks in public reduced the daily number of coronavirus by as much as 2% in Washington, D.C. and the 15 states that mandated face mask use compared to states that did not. The longer face mask mandates were in place, the study found there was a higher reduction in COVID-19 cases. Researchers also looked at 20 states that enacted employee-only mandates instead of public face mask use, but did not find a significant impact on the spread in those locations. The study was unable to measure the actual use of face masks in specific communities and researchers were only able to measure confirmed cases of COVID-19, despite evidence that infection rates in some areas were higher. Researchers from the University of Washington say universal face mask use could reduce the death toll from COVID-19 by 33,000. The university's latest projection says more than 179,000 Americans will die from coronavirus by Oct. 1. "For pretty much every state that we've looked at, if we can get people to wear masks, we can not only save lives, but I sort of think of it as we can also save the economy because we can keep business going," said Dr. Chris Murray of the University of Washington's Institute for Health Metrics and Evaluation. More than half of the U.S. is now seeing an increase in week-to-week cases, with California, Florida and Texas setting records for single-day coronavirus case reports."You need to understand COVID-19 is still here, it's spreading faster than ever before," Texas Gov. Greg Abbott said.Health experts say progress is being made on a vaccine, but, in the meantime, erring on the side of caution is best."We have evidence, early evidence, that masks can reduce transmission even up to six-fold," said Dr. Sanjay Gupta, CNN's chief medical correspondent. "I think it's clear that they can save lives."

While many Americans still debate whether or not to wear face masks, a new study found that face mask use has prevented thousands coronavirus cases.

The study, published in the journal Health Affairs, estimates between 230,000 and 450,000 COVID-19 cases were prevented in states that required face masks between April 8 and May 15.

Researchers said wearing face masks in public reduced the daily number of coronavirus by as much as 2% in Washington, D.C. and the 15 states that mandated face mask use compared to states that did not.

The longer face mask mandates were in place, the study found there was a higher reduction in COVID-19 cases.

Researchers also looked at 20 states that enacted employee-only mandates instead of public face mask use, but did not find a significant impact on the spread in those locations.

The study was unable to measure the actual use of face masks in specific communities and researchers were only able to measure confirmed cases of COVID-19, despite evidence that infection rates in some areas were higher.

Researchers from the University of Washington say universal face mask use could reduce the death toll from COVID-19 by 33,000.

The university's latest projection says more than 179,000 Americans will die from coronavirus by Oct. 1.

"For pretty much every state that we've looked at, if we can get people to wear masks, we can not only save lives, but I sort of think of it as we can also save the economy because we can keep business going," said Dr. Chris Murray of the University of Washington's Institute for Health Metrics and Evaluation.

More than half of the U.S. is now seeing an increase in week-to-week cases, with California, Florida and Texas setting records for single-day coronavirus case reports.

"You need to understand COVID-19 is still here, it's spreading faster than ever before," Texas Gov. Greg Abbott said.

Health experts say progress is being made on a vaccine, but, in the meantime, erring on the side of caution is best.

"We have evidence, early evidence, that masks can reduce transmission even up to six-fold," said Dr. Sanjay Gupta, CNN's chief medical correspondent. "I think it's clear that they can save lives."

Idaho did not meet the metrics to move forward to fewer restrictions, the governor said.

BOISE, Idaho Most of Idaho will remain in Stage 4 for at least two more weeks after the state failed to meet the benchmarks necessary to move forward, Gov. Brad Little announced Thursday.

The announcement came Thursday during a press conference Little called to address the state's Idaho Rebounds plan.

"The statewide approach to mitigating the spread of COVID-19 three months ago was the right thing to do. Three months ago, testing and contact tracing was limited, some areas of Idaho faced alarming healthcare capacity restraints, and there wasn't enough personal protective equipment on hand for businesses and healthcare workers," Little said. "But from the start, our plan was to eventually transition to a more regional approach in our response and that's what we've begun.

Stage 4 of coronavirus restrictions will be extended for those counties that were already in that stage. Ada County, however, has been moved back to Stage 3 by Central District Healthafter a spike of coronavirus cases.

"The goal all along has been to ensure our hospitals aren't overrun with people seriously ill from complications of this highly contagious respiratory disease," Little said. "You can engage in the economy, safely go back to work, and safely receive care from your medical provider, but you must do so while practicing the proven measures to fight the spread of coronavirus."

Health officials will reevaluate at the end of the two-week period to determine whether the state can move out of Stage 4. Little said it is crucial for every Idahoan to do their part to make sure that happens.

"We want businesses to reopen. We want our children back in school at the end of the summer," he said. "So please, do not let your guard down."

Watch Gov. Little's full news conference in the YouTube player below:

State Epidemiologist Dr. Christine Hahn said there is a rising trend in people going to the emergency room with "COVID-like" symptoms, as well as an increase in infections among healthcare workers.

Most of the health workers infected have been in Ada and Canyon counties, and are believed to have been exposed to the virus out in the community, rather than at their jobs.

"Our cases have been increasing pretty dramatically in the last two weeks, over the 14 days that we have measured here, you can see an increasing trend in cases," Hahn said.

Hahn added that Idaho has met the guidelines for healthcare capacity, meaning that hospitals have not yet become overtaxed by the number of patients. Currently, there are about 100 ICU beds and 400 ventilators still available, she said.

"Right now we are not using crisis standards of care in the hospitals," she said. "They are able to manage patients, they have enough ICU beds, they have enough ventilators - we're all good for now."

By Thursday morning, Idaho had reached 4,645 confirmed and probable cases statewide, with 215 new cases reported on Wednesday - the single largest one-day spike in cases since the outbreak began in March.

Little said he believed holding at Stage 4 was the right response to the jump in cases, rather than moving backwards to a previous stage, like what happened in Ada County. Nine counties in Idaho have not yet had a single confirmed COVID-19 case, he noted.

The governor says he hopes delaying the move out of Stage 4 will push Idahoans to adhere to social distancing and face-covering guidelines, and allow the state to get the upward trend of infections under control.

"We're not slamming on the brakes, we're tapping on the brakes," he said.

However, the governor said he is not considering implementing mandatory face-covering rules the way some neighboring states have.

"Mandatory masks just don't make any sense for a lot of Idaho," he said.

Little urged residents to say vigilant, noting that life may not completely return to normal even if cases trend downward again.

"We're going to have to have capacity in the fall, and as the days get shorter and people are more inside, we're going to have to do more," he said. "Hopefully, we'll know more about it. Hopefully, we'll have more therapeutics. Hopefully, a vaccine will be on the horizon - but if it isn't, we're going to have to ramp up our practices going forward."

At KTVB, were focusing our news coverage on the facts and not the fear around the virus. To see our full coverage, visit our coronavirus section, here: www.ktvb.com/coronavirus.

See our latest updates in our YouTube playlist:

Who and what next?

The coronavirus 2019 (COVID-19) pandemic has brought tighter restrictions on the daily lives of millions of people, but we do not yet understand what measures are the most effective. Zhang et al. modeled virus transmission in Wuhan, China, in February 2020, investigating the effects of interventions ranging from patient management to social isolation. Age-mixing patterns were estimated by contact surveys conducted in Wuhan and Shanghai at the beginning of February 2020. Once people reduced their average daily contacts from 14 to 20 down to 2, transmission rapidly fell below the epidemic threshold. The model also showed that preemptive school closures helped to reduce transmission, although alone they would not prevent a COVID-19 outbreak. Limiting human mixing to within households appeared to be the most effective measure.

Science, this issue p. 1481

Intense nonpharmaceutical interventions were put in place in China to stop transmission of the novel coronavirus disease 2019 (COVID-19). As transmission intensifies in other countries, the interplay between age, contact patterns, social distancing, susceptibility to infection, and COVID-19 dynamics remains unclear. To answer these questions, we analyze contact survey data for Wuhan and Shanghai before and during the outbreak and contact-tracing information from Hunan province. Daily contacts were reduced seven- to eightfold during the COVID-19 social distancing period, with most interactions restricted to the household. We find that children 0 to 14 years of age are less susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than adults 15 to 64 years of age (odds ratio 0.34, 95% confidence interval 0.24 to 0.49), whereas individuals more than 65 years of age are more susceptible to infection (odds ratio 1.47, 95% confidence interval 1.12 to 1.92). Based on these data, we built a transmission model to study the impact of social distancing and school closure on transmission. We find that social distancing alone, as implemented in China during the outbreak, is sufficient to control COVID-19. Although proactive school closures cannot interrupt transmission on their own, they can reduce peak incidence by 40 to 60% and delay the epidemic.

The novel coronavirus disease 2019 (COVID-19) epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan City, China, in December 2019 and quickly spread globally, with 2,063,161 cases reported in 185 countries or regions as of 16 April 2020 (1). A total of 82,692 cases of COVID-19, including 4632 deaths, have been reported in mainland China, including 50,333 cases in Wuhan City and 628 cases in Shanghai City (2). The epidemic in Wuhan and in the rest of China subsided after implementation of strict containment measures and movement restrictions, with recent cases originating from travel (3). However, key questions remain about the age profile of susceptibility to infection, how social distancing alters age-specific contact patterns, and how these factors interact to affect transmission. These questions are relevant to the choice of control policies for governments and policy-makers around the world. In this study, we evaluate changes in mixing patterns linked to social distancing by collecting contact data in the midst of the epidemic in Wuhan and Shanghai. We also estimate age differences in susceptibility to infection based on contact-tracing data gathered by the Hunan Provincial Center for Disease Control and Prevention (CDC), China. Based on these empirical data, we developed a mathematical disease transmission model to disentangle how transmission is affected by age differences in the biology of COVID-19 infection and altered mixing patterns owing to social distancing. Additionally, we project the impact of social distancing and school closure on COVID-19 transmission.

To estimate changes in age-mixing patterns associated with COVID-19 interventions, we performed contact surveys in two cities: Wuhan, the epicenter of the outbreak, and Shanghai, one of the largest and most densely populated cities in southeast China. Shanghai experienced extensive importation of COVID-19 cases from Wuhan as well as local transmission (4). The surveys were conducted from 1 February 2020 to 10 February 2020, as transmission of COVID-19 peaked across China and stringent interventions were put in place. Participants in Wuhan were asked to complete a questionnaire describing their contact behavior (5, 6) on two different days: (i) a regular weekday between 24 December 2019 and 30 December 2019, before the COVID-19 outbreak was officially recognized by the Wuhan Municipal Health Commission (used as baseline); and (ii) the day before the interview (outbreak period). Participants in Shanghai were asked to complete the same questionnaire used for Wuhan but only report contacts for the outbreak period. For the baseline period in Shanghai, we relied on a survey conducted in 20172018 that followed the same design (7). In these surveys, a contact was defined as either a two-way conversation involving three or more words in the physical presence of another person or a direct physical contact (e.g., a handshake). Details are given in the supplementary materials (SM, sections 1 and 2).

We analyzed a total of 1245 contacts reported by 636 study participants in Wuhan and 1296 contacts reported by 557 participants in Shanghai. In Wuhan, the average daily number of contacts per participant was significantly reduced, from 14.6 for the baseline period (mean contacts weighted by age structure: 14.0) to 2.0 for the outbreak period (mean contacts weighted by age structure: 1.9) (p < 0.001). The reduction in contacts was significant for all stratifications by sex, age group, type of profession, and household size (Table 1). A larger reduction was observed in Shanghai, where the average daily number of contacts decreased from 18.8 (mean contacts weighted by age structure: 19.8) to 2.3 (mean contacts weighted by age structure: 2.1). Although an average individual in Shanghai reported more contacts than one in Wuhan on a regular weekday, this difference essentially disappeared during the COVID-19 outbreak period. A similar decrease in the number of contacts was found in the United Kingdom during the COVID-19 lockdown period (8).

N is the number of participants who provided non-missing contact data.

The typical features of age-mixing patterns (6, 7) emerge in Wuhan and Shanghai when we consider the baseline period (Fig. 1, A and D). These features can be illustrated in the form of age-stratified contact matrices (provided as ready-to-use tables in the SM, section 3.6), where each cell represents the average number of contacts that an individual has with other individuals, stratified by age groups. The bottom left corner of the matrix, corresponding to contacts between school-age children, is where the largest number of contacts is recorded. The contribution of contacts in the workplace is visible in the central part of the matrix, and the three diagonals (from bottom left to top right) represent contacts between household members. By contrast, for the outbreak period when strict social distancing policies were in place, many of the above-mentioned features disappear, essentially leaving the sole contribution of household mixing (Fig. 1, B and E). In particular, assortative contacts between school-age individuals are fully removed, as illustrated by differencing baseline and outbreak matrices (Fig. 1, C and F). Overall, contacts during the outbreak mostly occurred at home with household members (94.1% in Wuhan and 78.5% in Shanghai). Thus, the outbreak contact matrix nearly coincides with the within-household contact matrix in both study sites, and the pattern of assortativity by age observed for regular days almost entirely disappears (SM, section 3.6). These findings are consistent with trends in within-city mobility data, which indicate an 86.9% drop in Wuhan and 74.5% drop in Shanghai between early January and early February (see SM, section 4). Such a large decrease in internal mobility is consistent with most of the contacts occurring in the household during the outbreak period. Of note, the strict social distancing measures implemented in Wuhan and Shanghai did not entirely zero out contacts in the workplace, because essential workers continued to perform their activities (as observed in our data; see SM, section 3.5).

(A) Baseline period contact matrix for Wuhan (regular weekday only). Each cell of the matrix represents the mean number of contacts that an individual in a given age group has with other individuals, stratified by age groups. The color intensity represents the number of contacts. To construct the matrix, we performed bootstrap sampling with replacement of survey participants weighted by the age distribution of the actual population of Wuhan. Every cell of the matrix represents an average over 100 bootstrapped realizations. (B) Same as (A), but for the outbreak contact matrix for Wuhan. (C) Difference between the baseline period contact matrix and the outbreak contact matrix in Wuhan. (D) Same as (A), but for Shanghai. (E and F) Same as (B) and (C), but for Shanghai.

The estimated mixing patterns are based on self-reported contacts that can thus be affected by various biases. In particular, reported contacts for the baseline period in Wuhan may be prone to recall bias because contacts were assessed retrospectively. Further, because of the retrospective nature of the baseline survey in Wuhan, we were unable to account for the lower number of contacts during weekends. The more complete data from Shanghai did not suffer recall bias and allowed us to weight contacts for weekdays and weekends; sensitivity analyses suggest that this has little impact on results (SM, section 8.3). Another possible bias is that survey participants may have felt pressure to minimize reported contacts that occurred during the outbreak, given that social distancing was in place and strictly enforced by the government, even if the anonymity and confidentiality of the survey were emphasized. However, results are robust to inflating reported contacts outside of the home severalfold, suggesting that these compliance and social acceptability biases linked to the outbreak period do not affect our main findings (SM, section 8.2). Another caveat is that in parallel to population-level social distancing measures, case-based interventions were implemented and could have affected contacts, including rapid isolation of confirmed and suspected cases and quarantine of close contacts for 14 days. However, only a small portion of the population in the two study sites was affected by contact tracing and quarantine, thus having little to no effect on average contact patterns in the general population.

Next, to understand the interplay between social distancing interventions, changes in human mixing patterns, and outbreak dynamics, we need to consider potential age differences in susceptibility to infection. This is currently a topic of debate, because little information on the age profile of asymptomatic cases is available (9, 10). To this aim, we analyzed COVID-19 contact-tracing information gleaned from detailed epidemiological field investigations conducted by the Hunan CDC (SM, section 5). Briefly, all close contacts of COVID-19 cases reported in Hunan province were placed under medical observation for 14 days and were tested using real-time reverse transcription polymerase chain reaction (RT-PCR). Those who tested positive were considered as SARS-CoV-2 infections. We estimated the odds ratios (ORs) for a contact of a certain age group to be infected, relative to a reference age group. We performed generalized linear mixed model regression to account for clustering and potential correlation structure of contacts exposed to the same index case (e.g., in the household). We included the age group and gender of a contact, type of contact, and whether the contact traveled to Hubei or Wuhan as regression covariates (SM, section 5). We found that susceptibility to SARS-CoV-2 infection increased with age. Young individuals (aged 0 to 14 years) had a lower risk of infection than individuals aged 15 to 64 years {OR = 0.34 [95% confidence interval (CI): 0.24 to 0.49], p < 0.0001}. By contrast, older individuals aged 65 years and older had a higher risk of infection than adults aged 15 to 64 years [OR = 1.47 (95% CI: 1.12 to 1.92), p = 0.005]. These findings are in contrast with a previous study in Shenzhen, where susceptibility to infection did not change with age (9).

Next, we explore how our data can inform control strategies for COVID-19. A key parameter regulating the dynamics of an epidemic is the basic reproduction number (R0), which corresponds to the average number of secondary cases generated by an index case in a fully susceptible population. We estimated the impact of interventions on R0, relying on our age-specific estimates of susceptibility to infection and contact patterns before and during interventions. We used the next-generation matrix approach to quantify changes in R0 (11) (SM, section 6). Additionally, to illustrate the impact of age-mixing patterns on the dynamics of the epidemic, we developed a simple SIR model of SARS-CoV-2 transmission (SM, section 6). In the model, the population is divided into three epidemiological categories: susceptible, infectious, and removed (either recovered or deceased individuals), stratified by 14 age groups. Susceptible individuals can become infectious after contact with an infectious individual according to the estimated age-specific susceptibility to infection. The rate at which contacts occur is determined by the estimated mixing patterns of each age group. The mean time interval between two consecutive generations of cases was taken to be 5.1 days, assuming it aligns with the mean of the serial interval reported by Zhang et al. (3).

In the early phases of COVID-19 spread in Wuhan, before interventions were put in place, R0 values were estimated to range between 2.0 and 3.5 (1218). In this analysis, we extended this range from 1 to 4 for the baseline period (i.e., before interventions). We find that the considerable changes of mixing patterns observed in Wuhan and Shanghai during the social distancing period led to a drastic decrease in R0 (Fig. 2). When we consider contact matrices representing the outbreak period, keeping the same baseline disease transmissibility as in the preintervention period, the reproductive number drops well below the epidemic threshold in Wuhan (Fig. 2A) and Shanghai (Fig. 2B). This finding is robust to relaxing assumptions about age differences in susceptibility to infection; the epidemic is still well controlled if SARS-CoV-2 infection is assumed to be equally likely in all age groups (Fig. 2, A and B). We also performed sensitivity analyses regarding possible recall and compliance biases of self-reported contacts as well as the definition of contact (i.e., considering only contacts lasting more than 5 min). The results are consistent with those reported here (SM, section 8).

(A) Estimated R0 during the outbreak (mean and 95% CI), as a function of baseline R0 (i.e., that derived by using the contact matrix estimated for the baseline period). The figure refers to Wuhan and includes both the scenario accounting for the estimated susceptibility to infection by age and the scenario where we assume that all individuals are equally susceptible to infection. The distribution of the transmission rate is estimated through the next-generation matrix approach by using 100 bootstrapped contact matrices for the baseline period to obtain the desired R0 values. We then use the estimated distribution of the transmission rate and the bootstrapped outbreak contact matrices to estimate R0 for the outbreak period. The 95% CIs account for the uncertainty on the distribution of the transmission rate, mixing patterns, and susceptibility to infection by age. (B) Same as (A), but for Shanghai. (C) Infection attack rate 1 year after the initial case of COVID-19 (mean and 95% CI) as a function of the baseline R0. The estimates are made by simulating the SIR transmission model (see SM) using the contact matrix for the baseline period and considering the estimated susceptibility to infection by age and assuming that all individuals are equally susceptible to infection. The 95% CIs account for the uncertainty on the mixing patterns and susceptibility to infection by age. (D) Same as (C), but for Shanghai.

In an uncontrolled epidemic (without intervention measures, travel restrictions, or spontaneous behavioral responses of the population) and for R0 in the range of 2 to 3, we estimate the mean infection attack rate to be in the range 53 to 92% after a year of SARS-CoV-2 circulation, with slight variation between Wuhan (Fig. 2C) and Shanghai (Fig. 2D). These estimates should be considered as an upper bound of the infection attack rate because they are based on a compartmental model that does not account for high clustering of contacts (e.g., repeated contacts among household members). If we consider a scenario in which social distancing measures are implemented early on, as the new virus emerges, the estimated R0 remains under the epidemic threshold and thus the epidemic cannot take off in either location. Furthermore, we estimate that the magnitude of interventions implemented in Wuhan and Shanghai would have been enough to block transmission for an R0 before the interventions of up to ~6 in Wuhan and ~7.8 in Shanghai.

Next, we use the model to estimate the impact of preemptive mass school closure. We considered two different contact pattern scenarios, based on data from Shanghai: contacts estimated during vacation periods (7) and contacts estimated during regular weekdays, after all contacts occurring in school settings have been removed (7). Both scenarios represent a simplification of a school closure strategy. Indeed, school closures in response to the COVID-19 pandemic in China have entailed interruption of all educational on-site services. However, mixing patterns measured during school vacations indicate that a fraction of children still attend additional educational activities, as is typical in Chinese cities. On the other hand, when removing all contacts in the school setting, we do not consider potential trickle-down effects on the mixing patterns of other age groups; for instance, parents may need to leave work to take care of school-age children. Our modeling approach indicates that limiting contact patterns to those observed during vacations would interrupt transmission for baseline R0 up to 1.5 (Fig. 3, A and C). Removing all school contacts would do the same for baseline R0 up to 1.2. If we apply these interventions to a COVID-19 scenario, assuming a baseline R0 of 2 to 3.5, we can achieve a noticeable decrease in infection attack rate and peak incidence and a delay in the epidemic, but transmission is not interrupted (Fig. 3, B and D). For instance, for a baseline R0 of 2.5 and assuming a vacation mixing pattern, the mean peak daily incidence is reduced by about 64%. In the corresponding scenario where school contacts are removed, we estimate a reduction of about 42%. Overall, school-based closure policies are not sufficient to entirely prevent a COVID-19 outbreak, but they can affect disease dynamics and hence hospital surge capacity. It is important to stress that individuals aged 5 to 19 years in Shanghai represent 9.5% of the population (19), markedly lower than the mean in China [16.8% (19)] and other countries [including Western countries; e.g., 19.7% in the United States (20)].

(A) Estimated R0 during the outbreak (mean and 95% CI), as a function of baseline R0 (i.e., that derived by using the contact matrix estimated for the baseline period). The figure refers to Shanghai and the scenario accounting for the estimated susceptibility to infection by age. Three contact patterns are considered: (i) as estimated during the COVID-19 outbreak, (ii) as estimated during school vacations (7), and (iii) as estimated for the baseline period, but suppressing all contacts at school. (B) Daily incidence of new SARS-CoV-2 infections (mean and 95% CI), as estimated by the SIR model, assuming age-specific susceptibility to infection (see SM). Three mixing patterns are considered: (i) as estimated for the baseline period, (ii) as estimated during school vacations (7), and (iii) as estimated for the baseline period, but suppressing all contacts at school. The inset shows the infection attack rate 1 year after the introduction of the first COVID-19 case (mean and 95% CI). (C) Same as (A), but assuming equal susceptibility to infection by age. (D) Same as (B), but assuming equal susceptibility to infection by age.

The results of this study should be considered in light of the following limitations. In our simulation model, we estimated the effect of social distancing alone; combining social distancing with other interventions would have a synergistic effect to even further reduce transmission. It is likely that population-wide social distancing, case-based strategies, and decontamination efforts all contributed to achieve control in Wuhan and Shanghai, and their effect is difficult to separate out in retrospective observational studies. Our estimates of age differences in susceptibility to infection are based on active testing of 7375 contacts of 136 confirmed index cases. These data suffer from the usual difficulties inherent to the reconstruction of epidemiological links and detection of index cases. Contact data are useful, but seroepidemiology studies will be essential to fully resolve population susceptibility profiles to SARS-CoV-2 infection and disease. Although the age patterns of contacts were similar in the two study locations during the COVID-19 outbreak period, these patterns may not be fully representative of other locations in China and abroad, where social distancing measures may differ. Because reliable estimates of the contribution of asymptomatic SARS-CoV-2 infections to transmission are still lacking, we did not explicitly model differences between symptomatic and asymptomatic individuals. We considered a serial interval of 5.1 days (3), based on a prior estimate from China, at a time when case-based and contact-tracing intervention measures were in place, which tends to shorten the interval between successive cases. However, this choice does not affect the estimated changes in reproduction number between the baseline and outbreak periods. Modeling results may underestimate the effect of social distancing interventions because our results concentrate on the number of contacts and ignore the type of social interactions (e.g., increased distance between individuals while in contact or use of a face mask), which may have changed owing to increased awareness of the population (21, 22). Finally, it is worth noting that our school closure simulations are not meant to formulate a full intervention strategy, which would require identification of epidemic triggers to initiate closures and evaluation of different durations of intervention (6). Nonetheless, our modeling exercise provides an indication of the possible impact of a nationwide preemptive strategy on the infection attack rate and peak incidence. To generalize these findings to other contexts, location-specific age-mixing patterns and population structures should be considered. Perhaps most importantly, strict lockdown strategies of the kind implemented in Wuhan, Shanghai, and other regions of the world are extremely disruptive economically and mentally, and more targeted approaches to block transmission are preferable in the long run. We do not necessarily endorse blunt lockdown policies here; we merely describe their impact on COVID-19 transmission based on the Chinese experience.

Our study provides evidence that the interventions put in place in Wuhan and Shanghai, and the resulting changes in human behavior, drastically decreased daily contacts, essentially reducing them to household interactions. This led to a dramatic reduction of SARS-CoV-2 transmission. As lockdown measures are put in place in other locations, human mixing patterns in the outbreak period could be captured by data on within-household contacts, which are available for several countries around the world (57, 2325). Moving forward, it will be particularly important to design targeted strategies for long-term control of COVID-19, including school- and work-based control strategies, along with large-scale testing and contact tracing (2628). Research should concentrate on refining age-specific estimates of susceptibility to infection, disease, and infectiousness, which are instrumental to evaluating the impact of these strategies.

J. Zhang, M. Litvinova, Y. Liang, Y. Wang, W. Wang, S. Zhao, Q. Wu, S. Merler, C. Viboud, A. Vespignani, M. Ajelli, H. Yu, Data and code for changes in contact patterns shape the dynamics of the novel coronavirus disease 2019 outbreak in China. Zenodo (2020);.doi:10.5281/zenodo.3775672

M. J. Keeling, P. Rohani, Modeling Infectious Diseases in Humans and Animals (Princeton Univ. Press, 2011), chap. 3.

A. Agresti, An Introduction to Categorical Data Analysis (Wiley, 2018).

R. Anderson, R. May, Infectious Diseases of Humans: Dynamics and Control (Oxford Univ. Press, 1991).

Minks at a mink farm. Yuri Tutov /AFP via Getty Images hide caption

Minks at a mink farm.

Minks on two fur farms in the Netherlands began getting sick in late April. Some were coughing, with runny noses; others had signs of severe respiratory disease. Soon, they started dying.

Researchers took swabs from the animals and dissected the ones that had died.

The culprit: SARS-COV-2, the novel coronavirus causing a global pandemic.

It's part of an emerging pattern of animals getting infected with the novel coronavirus with a new concern: The minks are thought to have passed the disease back to humans. Since the discovery, more than 500,000 minks have been culled on fur farms in the Netherlands over worries that their mink populations could spread the virus among humans.

The minks were first exposed to the coronavirus by infected farm workers, according to Wim van der Poel, a veterinarian who studies viruses at Wageningen University & Research in the Netherlands. Then the virus spread among the animals in the farms like wildfire.

"The animals are in cages with wire tops and closed walls between them," says Van der Poel, who co-authored a Eurosurveillance paper investigating the mink farm infections that was published this month. "So it probably spread through droplet or aerosol transmission, from the top of one cage to another, when an animal is coughing or heavily breathing."

The Netherlands is one of the world's top exporters of mink fur for coats and trim. The outbreak was first reported on two of its approximately 125 farms and has now been found in at least 17. Van der Poel says the virus was likely spread to more farms either from infected workers who traveled between locations or from virus-contaminated products that moved from one farm to another.

Minks are the latest addition to the list of animals that we know can be infected with the novel coronavirus, says Linfa Wang, director of the emerging infectious diseases program at Duke-NUS Medical School in Singapore. "The first one we noticed was cats," he says. "Then it was followed by dogs, which are susceptible but not as much as cats. And then the tigers in the New York zoo. And now the minks." Laboratory experiments have also confirmed that hamsters and some monkeys can also get sick from the virus. And the virus is believed to have originated in Chinese horseshoe bats.

The findings from the mink farm adds an concerning layer to our understanding of how the virus spreads because infected minks are thought to have passed the virus back to people, according to Dutch government reports. At least two farm workers are believed to have caught the novel coronavirus from handling the minks or breathing virus-contaminated clouds of dust.

The situation confirms a longstanding concern among researchers which has, until now, been hypothetical: In some animal-to-human interactions, the virus can transmit both ways. "It's another route of transmission that we have to worry about," says Kevin Olival, an ecologist at EcoHealth Alliance, a nonprofit that monitors for emerging diseases. "And if the virus somehow establishes itself in animal populations or in other wildlife populations around the world, it'll be really hard to eradicate it if it keeps spilling back into the human population."

Those concerns prompted Dutch authorities to cull all the minks on farms where the novel coronavirus has been found. While many of the animals on affected farms were found to have survived the virus and developed antibodies, it's unclear how long they might be protected. And many new pups, presumed to be susceptible to the coronavirus, are born in the late spring, van der Poel says. So hundreds of thousands of animals are being gassed to ensure that they do not become reservoirs for the virus.

From a disease control perspective, Wang says it's helpful that the outbreaks were contained to farms and caused symptoms in the infected animals, "so at least you notice the animal is sick." A less controllable scenario, he says, is if the virus takes root in wandering wildlife populations for instance, if it were to become established among North American bats, a group that could carry the disease without developing symptoms and spread it widely.

Wang sees this ability of the novel coronavirus to jump easily between different species as troubling especially since the virus has spread so rapidly among humans. Many common viruses, such as measles and hepatitis, mostly infect humans. On the other hand, some emerging viruses such as Ebola, Nipah and SARS infect a broad spectrum of species. But outbreaks among humans have been contained.

When it comes to eradicating a disease, "the worst is an animal virus that jumps over and becomes established in humans and has a wide host range," Wang says, meaning it can infect many different animal species that might pass it back to humans. "And that's SARS-COV-2."

Currently, the novel coronavirus is mainly spreading through close contact between people, says Maria Van Kerkhove, technical lead for the World Health Organization's health emergencies program.

Still, researchers think the potential for animal reservoirs is something public health officials should be thinking about now. The lesson from the mink farms, says van der Poel, is that we should be testing all kinds of animals for the novel coronavirus as well as keeping a lookout for other novel diseases they may be carrying.

"We have to have an open mind and open eyes for any new virus that pops up," he says.

Jerome Socolovsky contributed to this story.

The true number of Americans who've been infected with COVID-19 may top 20 million, according to new estimates from the Centers for Disease Control and Prevention.

"Our best estimate right now is that for every case that's reported, there actually are 10 other infections," Dr. Robert Redfield, director of the CDC, said on a call with reporters Thursday.

Full coverage of the coronavirus outbreak

The assessment comes from looking at blood samples across the country for the presence of antibodies to the virus. For every confirmed case of COVID-19, 10 more people had antibodies, Redfield said, referring to proteins in the blood that indicate whether a person's immune system has previously fought off the coronavirus.

Those samples aren't just from people who have had antibody testing. They also come from testing performed on donated blood at blood banks or from other laboratory testing of blood.

Currently, there are 2.3 million COVID-19 cases reported in the U.S. The CDC's new estimate pushes the actual number of coronavirus cases up to at least 23 million.

"This virus causes so much asymptomatic infection," Redfield said. "The traditional approach of looking for symptomatic illness and diagnosing it obviously underestimates the total amount of infections."

Let our news meet your inbox. The news and stories that matters, delivered weekday mornings.

The estimation comes amid rises in cases across the Southeast and Western U.S., particularly among younger adults in their 20s, 30s and 40s.

Download the NBC News app for full coverage of the coronavirus outbreak

Also Thursday, the CDC expanded its list of who is at greatest risk for COVID-19 complications, removing the age cutoff of 65.

"There's not an exact cutoff of age at which people should or should not be concerned," Dr. Jay Butler, head of the COVID-19 response at the CDC, said. Rather, a person's risk increases with age, but that doesn't preclude younger adults from complications.

Indeed, people of any age with certain underlying health conditions have a higher risk, though the likelihood of having these conditions increases with age. At risk are those with heart disease, chronic kidney disease, chronic obstructive pulmonary disease, obesity, type 2 diabetes, sickle cell disease and anyone with a compromised immune system.

CDC also clarified the list of other conditions that might increase a persons risk of severe illness, including asthma, high blood pressure, neurologic conditions such as dementia, cerebrovascular disease such as stroke, and pregnancy.

Research published on Thursday from the CDC specifically addressed the risk in pregnant women. When compared to nonpregnant women with the virus, pregnant women with COVID-19 were more likely to be hospitalized, admitted to the intensive care unit and put on a ventilator.

Death rates between the two groups of women, however, were similar.

Redfield also urged Americans to be vigilant about behavior measures known to minimize spread of the coronavirus, particularly as the country heads into the July Fourth holiday.

The coronavirus spreads mainly from person to person through respiratory droplets from coughing, sneezing, talking and singing.

"The most powerful tool that we have is social distancing," he said. That means maintaining a physical distance of at least 6 feet in public, wearing face coverings and regular hand-washing.

"If you must go out into the community, being in contact with fewer people is better than many," Redfield added.

Follow NBC HEALTH on Twitter & Facebook.

Erika Edwards is a health and medical news writer and reporter for NBC News and "TODAY."

The reports seemed to take doctors by surprise: The respiratory virus that causes Covid-19 made some patients nauseous. It left others unable to smell. In some, it caused acute kidney injury.

As the pandemic grew from an outbreak affecting thousands in Wuhan, China, to some 10 million cases and 500,000 deaths globally as of late June, the list of symptoms has also exploded. The Centers for Disease Control and Prevention constantly scrambled to update its list in an effort to help clinicians identify likely cases, a crucial diagnostic aid at a time when swab tests were in short supply and typically took (and still take) days to return results. The loss of a sense of smell made the list only in late April.

For many diseases, it can take years before we fully characterize the different ways that it affects people, said nephrologist Dan Negoianu of Penn Medicine. Even now, we are still very early in the process of understanding this disease.

advertisement

What they are understanding is that this coronavirus has such a diversity of effects on so many different organs, it keeps us up at night, said Thomas McGinn, deputy physician in chief at Northwell Health and director of the Feinstein Institutes for Medical Research. Its amazing how many different ways it affects the body.

One early hint that that would be the case came in late January, when scientists in China identified one of the two receptors by which the coronavirus, SARS-CoV-2, enters cells. It was the same gateway, called the ACE2 receptor, that the original SARS virus used. Studies going back some two decades had mapped the bodys ACE2 receptors, showing that theyre in cells that line the insides of blood vessels in what are called vascular endothelial cells in cells of the kidneys tubules, in the gastrointestinal tract, and even in the testes.

advertisement

Given that, its not clear why the new coronavirus ability to wreak havoc from head to toe came as a surprise to clinicians. Since ACE2 is also the receptor for SARS, its expression in other organs and cell types has been well-known, said Anirban Maitra of MD Anderson Cancer Center, who led a study mapping the receptor in cells of the GI tract. (Maitra is an expert in pancreatic cancer and, like many scientists this year, added Covid-19 to his research.)

Infecting cells is only the first way SARS-CoV-2 wreaks havoc. Patients with severe Covid-19 also suffer a runaway inflammatory response and, often, clot formation, said infectious disease physician Rochelle Walensky of Massachusetts General Hospital. That can cause symptoms as different as a lack of blood flow to the intestines and the red, inflamed Covid toe.

Weve had five cases of patients whove had to have their gut removed, Walensky said. You see these cases and you say, wait a minute; the virus is doing this, too? It has definitely been keeping us on our toes.

Venky Soundararajan had a hunch that the extent of ACE2 distribution throughout the body was lying in plain sight. The co-founder and chief scientific officer of nference, which uses artificial intelligence to mine existing knowledge, he and his colleagues turned their system into a hunt for ACE2 knowledge. Combing 100 million biomedical documents from published papers to genomic and other -omics databases, they uncovered multiple tissues and cell types with ACE2 receptors, they reported last month in the journal eLife.

They also calculated what percent of each cell type expresses reasonable amounts of ACE2, Soundararajan said. On average, about 40% of kidney tubule cells do, and in a surprise for a respiratory virus, cells in the GI tract were the strongest expressors of ACE2 receptors, he said.

The data mining found that ACE2 is also expressed in the noses olfactory cells. Thats not a new finding per se the nference system found it in existing databases, after all but it hadnt been appreciated by scientists or clinicians. It explains the loss or altered sense of smell that Covid-19 patients experience. Its importance became clear earlier this month, when scientists at the Mayo Clinic and nference reported that loss of a sense of smell is the earliest signature of Covid-19, appearing days before a positive swab test.

That study, using health records of 77,167 people tested for Covid-19, showed how the assumption that infection would first and foremost cause respiratory symptoms was misplaced. In the week before they were diagnosed, Covid-19 patients were 27 times more likely than people who tested negative for the virus to have lost their sense of smell. They were only 2.6 times more likely to have fever or chills, 2.2 times more likely to have trouble breathing or to be coughing, and twice as likely to have muscle aches. For months, government guidelines kept people not experiencing such typical signs of a respiratory infection from getting tested.

Faced with a disease the world had never seen before, physicians are learning as they go. By following the trail of ACE2 receptors, they are more and more prepared to look for, and treat, consequences of SARS-CoV-2 infection well beyond the obvious:

Gut: The coronavirus infects cells that line the inside of the large and small intestine, called gut enterocytes. That likely accounts for the diarrhea, nausea, and abdominal pain that about one-third of Covid-19 patients experience, said MD Andersons Maitra: The GI symptoms reflect physiological [dysfunction] of cells of the lower GI tract.

Why dont all patients have GI symptoms or indeed, the whole panoply of symptoms suggested by the near ubiquity of ACE2 receptors? For those with mild to moderate Covid-19, the infectious load in the GI tract may simply not be sufficient to cause symptoms, Maitra said.

Kidney: The cells lining the tubules that filter out toxic compounds from the blood are rife with ACE2 receptors. Last month, scientists studying 1,000 Covid-19 patients at a New York City hospital reported that 78% of those in intensive care developed acute kidney injury.

Smell: An analysis of 24 studies with data from 8,438 Covid-19 patients from 13 countries found this month that 41% had lost their sense of taste or smell, or both. That shouldnt be surprising, said Fabio Ferreli of Humanitas University in Milan: Perhaps the highest levels of ACE2 receptors are expressed in cells in the nasal epithelium. The sensory loss isnt due to nasal inflammation, swelling, or congestion, he said, but to direct damage to these epithelial cells. Loss of smell also impacts taste, but the virus may also have a direct effect on taste: The nference analysis found high levels of the ACE2 gene in tongue cells called keratinocytes, which contribute to the sense of taste.

There is another implication of the high expression of ACE2 in olfactory epithelium cells, scientists at Johns Hopkins concluded in a paper posted to the preprint site bioRxiv last month: ACE2 levels in the olfactory epithelium of the upper airways that are 200 to 700 times higher than in the lower airways might explain the viruss high transmissibility. It was weeks before experts recognized that the virus could spread from person to person.

Lungs: This is where a respiratory virus should strike, and SARS-CoV-2 does. The lungs type II alveolar cells among other jobs, they release a compound that allows the lungs to pass oxygen to the blood and take carbon dioxide from it are studded with ACE2 receptors. Once infected with the coronavirus, they become dysfunctional or die, and are so swarmed by immune cells that this inflammatory response can explode into the acute respiratory distress syndrome (ARDS) that strikes many patients with severe Covid-19, Walensky said.

There is new evidence that the virus also attacks platelet-producing cells, called megakaryocytes, in the lungs. In a study published on Thursday, pathologist Amy Rapkiewicz of NYU Winthrop Hospital found something she had never seen before: extensive clotting in the veins and other small blood vessels of patients hearts, kidneys, liver, and lungs. She suspects that the platelets produced by infected megakaryocytes travel through the bloodstream to multiple organs, damaging their vasculature and producing potentially fatal clots. You see that and you say, wow, this is not just a respiratory virus,' Rapkiewicz said.

Pancreas: In April, scientists in China reported that there was higher expression of the gene for ACE2 in the pancreas than in the lungs. Genetic data are an indirect measure of ACE2 receptors themselves, but could have been a tip-off to physicians to monitor patients for symptoms there. As it happens, the Chinese researchers also found blood markers for pancreas damage in Covid-19 patients, including in about 17% of those with severe disease.

Heart: Patients with severe Covid-19 have a high incidence of cardiac arrests and arrhythmias, scientists at the Perelman School of Medicine at the University of Pennsylvania recently found. Thats likely due to an extreme inflammatory response, but there might be more direct effects of the coronavirus, too. A large team of European researchers reported in April that arrhythmia (including atrial fibrillation), heart injury, and even heart failure and pulmonary embolism might reflect the fact that ACE2 receptors are highly expressed in cells along the inside walls of capillaries. When these vascular endothelial cells become infected, the resulting damage can cause clots, MGHs Walensky said, which in turn can cause Covid toe, strokes, and ischemic bowel (too little blood flow to the gut). Studies from around the world suggest that 7% to 31% of Covid-19 patients experience some sort of cardiac injury.

Gallbladder: Specialized cells in this organ, too, have high levelsof ACE2 receptors. Damage to the gallbladder (like the pancreas) can cause digestive symptoms.

With the number of Covid-19 patients closing in on 10 million, physicians fervently hope the virus has no more surprises in store. But theyre not counting on it.

Ive seen patients every day during this crisis, said Northwells McGinn. There have been times when Ive said, wait, the virus cant do anything new and then theres a young woman with a stroke or an older man with myocarditis, inflammation of the heart muscle. I keep thinking Im going to run out of material for the teaching videos he does on Covid-19, but it hasnt happened.

An updated map of state hot spots is available based on our analysis of more recent data.

There is growing concern about rising COVID-19 cases and other troubling trends in a subset of states that have reopened, and a few Governors and Mayors have either paused reopening or signaled their intention to do. Understanding in which states the pandemic is moving in the wrong, or right, direction, is critical but complex, as no single metric can tell the full story. For example, an increasing number of cases could be the result of more testing or the result of increasing transmission, or a combination of both.

A few existing resources examine state-level data to make assessments about current risk levels (see, in particular, https://www.covidexitstrategy.org/, https://covidactnow.org/, and https://www.aei.org/covid-2019-action-tracker/). We similarly sought to examine current trends across the U.S. and identify state hotspots for COVID-19. Specifically, we looked at two metrics that are readily available for all states and, when taken together, signal concern:

For each metric, we examined data from the most recent 14-day period to account for the lag between transmission and the incubation period of the virus, as well as the time at which an individual seeks and receives testing and testing results are reported to health officials; even so, it is important to note that cases from the most recent two-week period still reflect prior transmission patterns. We calculated the percent change based on a 7-day rolling average, which helps to account for fluctuations in reporting throughout each week and other noise in the data. We excluded states for which the percent change in at least one of the 14-day metrics was below 5%.

In addition to cases and positivity rates, we also include data on the percent change in the number of tests conducted, hospitalizations, and deaths, to provide additional context for interpreting trends. For example, hospitalization data provide information on severity of illness and strain on the health care system, though not all states report this information and it is a lagging measure that reflects transmissions from even longer ago. Increasing cases in the most recent period is likely predictive of future hospitalizations (and deaths), though depends on the characteristics or people being infected in any given area (since older people and those with pre-existing conditions are more likely to get severely ill once infected).

Looking at the period from June 8 to June 22, 20 states are classified as hotspots (i.e., have increasing cases and increasing positivity rates over the most recent 14-day period). See Figure and Table 1 below. These states are primarily in the West (9) and South (8); three are in the Midwest. Most are states that were not hit hard earlier in the pandemic. While four of the states are reporting fewer than 40 daily cases, nine are reporting 400 or more new cases per day, and 13 states have positivity rates above the recommended WHO 5% threshold. Outside of these hotspots, an additional four states have either increasing cases or positivity rates, coupled with increasing hospitalizations and/or deaths, which could be a cause for concern.

There are likely multiple policy, epidemiologic, and other factors driving these increases, including: when stay-at-home orders were lifted (and how long they were in place); the pace of reopening; the use of other social distancing measures (such as face mask requirements); increased population movement due to warming weather; outbreaks in congregate settings; the Memorial Day Holiday period; and, potentially, protests. For example, while 16 of the 20 states had lifted their stay-at-home orders by the end of May (California, Hawaii, and Oregon have maintained their stay-at-home orders as they have begun phased reopening), they did so at different paces (see Table 1). Many moved quickly, reopening businesses and lifting other restrictions within a two-week period. All states, except California, have lifted or eased bans on large gatherings and many have not required face masks, or have only recently done so after concerns were raised about rising cases. However, teasing out the role of these various factors and policy changes, many of which occurred simultaneously, will require further analysis.

Using these two metrics increasing COVID-19 cases and positivity rates over the most recent 14-day period, we find that almost 40% (20 states) are moving in the wrong direction. These hotspot states are primarily in the South and West, and most were not hit hard in the earliest days of the U.S. outbreak. Rising cases seen in these states now likely reflect an increase in transmission that began before the most recent two-week period and suggest that increasing hospitalizations could follow. In addition, their rising positivity rates indicate that the growth in cases is not due to increased testing and likely reflects an actual increase in transmission.

While these trends are concerning, and beginning to drive the national trend, most states (27) are moving in the right direction. Many of these states were among the last to reopen. Some phased in reopening over a longer time period and many have required the widespread use of face masks.

The factors determining which states are hotspots and which are not are difficult to tease out, but the inescapable reality is that the epidemic is getting worse, not better, in a significant portion of the country.

By: Anna Abram, Deputy Commissioner for Policy, Legislation, and International Affairs and Mark Abdoo, Associate Commissioner for Global Policy and Strategy

The European Union (EU) is one of the U.S. Food and Drug Administrations most important collaborators in tackling public heath challenges. The FDA and the European Commission (EC) and its European Medicines Agency (EMA) have long leveraged each others expertise and experience to promote the safety, effectiveness, and quality of medical products to advance the health of our citizens. Now, our work, built together over more than a decade, has paved the way for a multitude of critical collaborations on many scientific and regulatory fronts as part of our COVID-19 response.

What has helped drive this collaboration are the 30 technical expert groups, or clusters that the FDA and the EMA have established since 2003. These clusters meet regularly for regulatory discussions held under confidentiality commitments and were well positioned to pivot to focus on COVID-19 because of our ongoing work together. Since the start of the pandemic, many of these groups which often also include regulatory authorities from Japan, Canada, Australia, and other countries have shifted their work priorities to focus on COVID-19. For example, our expert group on vaccines has expanded into a multilateral forum to discuss regulatory issues related to the development of SARS-CoV-2 vaccines, whereas the pharmacovigilance group has begun to identify opportunities for collaboration on observational studies related to COVID-19 natural history and interventions. Similarly, our standing meetings on blood products are now focusing on developments related to COVID-19 convalescent plasma. The drug shortages discussions revolve around information sharing on strategies for COVID-19 related shortages and supply disruptions of medicines.

In these expert group discussions, the FDA and the EMA have been exchanging information on the rapidly evolving scientific landscape of products and clinical trials and, as possible, discussing the interpretation of data supporting regulatory decisions. For example, two days after the release of results from a clinical trial that the National Institute of Allergies and Infectious Diseases (NIAID-ACTT study) conducted, the FDA authorized the emergency use of the investigational antiviral drug remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. The FDA subsequently hosted a virtual meeting of key regulatory partners, including from Europe, Canada, and Japan, to discuss the safety and efficacy of remdesivir as a treatment for COVID-19. At the time, Japan had announced their version of early access to the drug and most of the other participating authorities were about to begin their own reviews for making such a decision, with EMA issuing a recommendation to expand remdesivir compassionate use shortly thereafter.

Against this backdrop of robust collaboration, on June 18-19, the FDA hosted virtual bilateral meetings with the EC and EMA to review progress on ongoing activities and share horizon scanning across high-priority areas. For example, public and private sector entities are proactively exploring strategic partnerships to address the anticipated challenges related to manufacturing and rapid scale-up of potential COVID-19 vaccines or therapeutics. As two-prominent international regulatory bodies, the FDA and the EC/EMA can help inform global regulatory strategies to accelerate production and global access of products. In addition, the application of real-world data to understand the natural history of COVID-19, treatment patterns, and the performance of diagnostics is of keen interest for both the FDA and the EU.

The FDA and the EU are also promoting engagement with global regulators, under the International Coalition of Medicines Regulatory Authorities (ICMRA) forum, which is comprised of 28 regulatory authorities from around the globe. For example, in March, as vaccine candidates began to be identified, the FDA and the EMA jointly chaired the first global regulators meeting to discuss regulatory strategies to facilitate the development of SARS-CoV-2 vaccines. Subsequent ICMRA workshops that are focused on COVID-19 therapeutic development, observational studies, and real-world data as well as policy approaches are helping to support mutual awareness and consideration of potential guidance alignment. Such vigorous efforts are reflected in the ICMRA joint statement, which was issued in April 2020, with global regulatory authorities expressing their collective support in countering COVID-19.

To maintain strong oversight of foreign-manufactured medical products, the FDA is leveraging inspection reports completed by the EU and United Kingdom under the Pharmaceutical Annex to the US-EU Mutual Recognition Agreement (MRA). The MRA creates an environment in which FDA and the EU may rely on inspections performed by each others regulatory authorities to inform our regulatory decisions, such as drug approvals or addressing drug shortages.

We are also leveraging our international collaborations in our medical device work. The FDA and global partners (including the EC and other European partners) regularly exchange information on medical device safety issues and regulatory developments. These international relationships have never been more important as we work to maintain critical supplies of medical devices such as personal protective equipment, ventilators and ventilator accessories, as well as diagnostic testing supplies and test kits for COVID-19. Our interactions have included working through our embassies and European contacts to address supply chain disruptions, medical device shortages, and removal of fraudulent and poor-quality products from the market. Moving forward, shared learnings about antibody tests, otherwise known as serology tests their validation, results of ongoing epidemiological studies, and potential use in broader testing programs will inform our continued efforts to confront this pandemic.

Our work in these endeavors is, as always, rooted in the FDAs unwavering commitment to helping to foster the development of safe and effective medical products. We recognize the shared challenges of public health authorities across the world in fighting this pandemic as well as the tremendous opportunities to accelerate our mission critical work through robust scientific collaboration. We will continue to collaborate with our global regulatory counterparts as we seek to bring safe and effective COVID-19 vaccines and treatments to our citizens as quickly as possible and as part of advancing our vital mission to protect and promote public health.