Updates on the COVID-19 pandemic from the Johns Hopkins Center for Health Security.
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EPI UPDATE The WHO COVID-19 Dashboard reports 56.62 million cases and 1.36 million deaths as of 10am EST on November 20. The daily global mortality has increased more than 80% since October 16, now up to more than 9,300 deaths per day—or one COVID-19 death every 9.2 seconds. This also corresponds to 1.2 daily deaths per million people—or one for every 830,000 people.
While the Northern Hemisphere COVID-19 surge continues in many countries, some are beginning to show signs that they have turned a corner and are beginning to gain some measure of control of their respective COVID-19 epidemics. Over the past 2 weeks, a number of countries are reporting decreasing daily incidence after implementing more restrictive mitigation measures. In Europe, the overall biweekly change across the continent is still positive, with a 9% increase compared to 2 weeks ago, but it is trending steadily downward. Despite the overall increase, 13 European countries are reporting decreasing trends in daily incidence over the past 2 weeks: Andorra (-30%), Belgium (-61% compared to 2 weeks ago), the Czech Republic (-47%), France (-19%), Iceland (-71%), Ireland (-43%), Luxembourg (-16%), the Netherlands (-40%), Slovakia (-32%), Slovenia (-15%), Spain (-16%), and Switzerland (-21%). Conversely, Canada and the US are reporting increasing incidence of 53% and 75%, respectively, over the past 2 weeks.
Looking at these countries, it is clear for most that they recently passed a peak in daily incidence. Even Europe as a whole, which is still reporting elevated incidence compared to 2 weeks ago, is beginning to show evidence that it could be approaching a peak in the current surge. Many European countries continue to report increasing trends in incidence, so the surge is far from over; however, even those still reporting increases have made progress, particularly compared to where they were in late October. Additionally, some countries are beginning to show indication that they are peaking in terms of daily COVID-19 mortality. While most are not yet reporting a negative biweekly change, the relative change is trending downward in most of these countries, and some are on track to transition to negative values in the near future. The mortality surges in Andorra and Iceland were much smaller in magnitude or duration than other European countries, and both have returned to essentially zero average deaths per day. Belgium’s and the Czech Republic’s daily incidence peaked slightly before most of the other countries on this list, and they appear to have recently passed a corresponding peak in mortality. The Netherlands and Slovakia appear to be at or near a peak as well, and France and Spain are exhibiting signs that they could be approaching their own peak. As a whole, Europe is still reporting increasing daily COVID-19 mortality, but it does appear to have passed an inflection point. As countries move further past their peak incidence, we expect mortality trends to follow.
In North America, Mexico is also reporting a decrease in daily incidence, down 6% compared to 2 weeks ago. Mexico exhibited a much sharper surge beginning in mid-to-late October, and it has reported decreasing daily incidence for 7 consecutive days. Until recently, Mexico’s daily mortality continued to increase, but it has reported decreasing mortality for 3 consecutive days. This is a fairly sharp decrease, especially considering the rate of increase only 3 days ago, so additional data are needed to determine if this is a temporary anomaly or the beginning of a longer-term trend.
UNITED STATES
The US CDC reported 11.47 million total cases and 249,670 deaths. The US is averaging more than 160,000 new cases per day, which equates nearly 1 million cases every 6 days. We expect the US to surpass 250,000 cumulative deaths in this afternoon’s update. From the first reported death on February 29, it took 55 days to reach 50,000 deaths. From there:
50k to 100k deaths- 33 days
100k to 150k deaths- 63 days
150k to 200k deaths- 55 days
200k to 250k deaths- 58 days
While the time from 150-200,000 deaths was shorter than from 200-250,000 deaths, the daily mortality has increased substantially over the past several weeks. When the US surpassed 200,000 deaths on September 22, the US mortality was near the end of its decline after the summer resurgence, at 746 deaths per day and on its way down to 700, where it held steady from September 30 to October 18. From there, the daily COVID-19 mortality has increased more than 70%. Notably, 250,000 deaths corresponds to one COVID-19 death for every 1,333 people in the US. Additionally, COVID-19 is estimated to be the third leading cause of death in the US. Based on US CDC data from 2018, the top 3 leading causes of death were heart disease (655,381 deaths), cancer (599,274), and accidents and unintentional injury (167,127).
Two-thirds of all US states have reported more than 150,000 cumulative cases, and 20 have reported more than 200,000 cases:
Florida’s COVID-19 dashboard is reporting more than 900,000 cases, and South Carolina’s and Iowa’s are reporting more than 200,000 total cases. We expect these to be reflected in the CDC data soon. We also anticipate that Massachusetts will surpass 200,000 cases in the near future.
SWEDEN The Swedish government approved a measure to limit public gatherings and events to a maximum of 8 individuals and removed existing exemptions for restaurants or other settings. One notable exception remains in place for funerals, which are limited to 20 individuals. The restrictions will begin on November 24 and builds on a previous decision to prohibit alcohol sales after 10pm to reduce gatherings at bars and restaurants. The new limit on gatherings is a drastic shift from the previous limit on events of more than 300 people, signaling a change in how Swedish authorities are approaching the national COVID-19 response. Sweden was previously known for having a relatively lax set of social distancing recommendations and measures, compared to many other countries, but Prime Minister Stefan Lofven recently urged Swedes to avoid settings like gyms, libraries, and even hosting dinners.
Sweden’s approach thus far has largely leaned on restrictions implemented at the regional level. The change in policy comes after substantial increases in COVID-19 incidence in recent months, and the restrictions are currently scheduled to last for 4 weeks. Sweden has reported 208,295 cases and 6,406 deaths, and it has reported exponential increases in daily incidence since mid-September—setting new records—and increasing daily mortality since mid-October.
NETHERLANDS Following a recent decline in daily incidence, an encouraging sign as Europe continues to battle the ongoing surge, the Netherlands is looking to relax some social distancing restrictions but maintaining a “partial lockdown” in place. Restaurants, bars, and cafes will remain closed, gatherings will still be limited to a maximum of 4 people, and households will continue to be limited to 3 visitors each day. Museums, theaters, and amusement parks may begin to reopen, albeit with limitations on capacity. The “partial lockdown” has been in place since mid-October, and it has limited indoor gatherings to 30 people, restricted hours for retail stores, and mandated mask use indoors for individuals aged 13 years and older. When the Netherlands instituted the “partial lockdown,” it was reporting one of the highest per capita incidence rates in the world. Since that time, however, the daily incidence decreased considerably, down from a peak of 10,000 new cases per day at the end of October to 5,200.
JAPAN Japanese Prime Minister Yoshihide Suga announced this week that the country is on “maximum alert,” following a concerning rise in the nation’s COVID-19 incidence. Japan is facing its “third wave” of COVID-19 and setting new records in terms of daily incidence. Earlier this week, Tokyo announced a “red alert” due to COVID-19, but a report by The New York Times indicated that this is largely symbolic (ie, to increase public awareness and adherence to recommended measures) rather than being associated with increased restrictions. Public health experts in Japan have expressed concern that this most recent surge warrants additional concern, beyond just the increase in incidence. In particular, the current surge is affected individuals of all ages, rather than being focused on younger adults, like the 2 previous waves. Japan’s response to this third wave has been an increased effort to encourage its citizens to be more vigilant with protective measures like mask wearing. Notably, Prime Minister Suga reportedly indicated that he does not intend to restrict businesses’ operating hours or eliminate government subsidies that aim to encourage people to travel and eat at local restaurants.
SYRIA Following years of domestic conflict that devastated the health system in some parts of the country, Syria is struggling to combat its COVID-19 epidemic. Over the course of the conflict, Syrian military forces have repeatedly targeted critical infrastructure and hospitals, as well as healthcare workers, which has left affected areas at high risk for disease spread. While a cease fire has temporarily halted the combat, healthcare workers have transitioned from treating trauma patients to COVID-19 patients. In Idlib, one of the last remaining areas controlled by opposition forces, COVID-19 incidence is reportedly increasing rapidly. The region was largely unaffected until July, but a report by the Associated Press (AP) indicates that it is now up to 300-500 new cases per day. The AP report also indicates that “infection rates jumped nearly twentyfold between September and October” and “climbed [another] 300%” since then*.
Limited testing capacity is available in the area—reportedly only 1,000 tests per day across 3 laboratories in Idlib—so the incidence is likely much higher than the reported figures. So far, most of the reported COVID-19 cases have been from cities, but health officials and experts are concerned that COVID-19 could spread rapidly in the densely populated camps, occupied by individuals and families displaced from their homes by the conflict. In Idlib, there are reportedly only 9 hospitals treating COVID-19 patients, serving a population of 4 million people. There are an additional 36 isolation and treatment centers, but these only provide basic care for mild illnesses.
Syria has reported an overall steady increase in daily incidence since June, with a minor surge in August and September. The overall trend is increasing exponentially, and the current daily incidence is now nearly back up to the peak of its summer surge. The official reports from the Syrian Ministry of Health indicate approximately 70 new cases per day nationwide, which is considerably lower than the media reports cited above. Syria is also reporting approximately 4 deaths per day.
VACCINES
ASTRAZENECA
The Oxford COVID Vaccine Trial Group (UK) published safety and efficacy data for the AstraZeneca/Jenner Institute (Oxford University) candidate SARS-CoV-2 vaccine. The study, published in The Lancet, discusses findings from the Phase 2 portion of the vaccine’s Phase 2/3 clinical trial, building on the Phase 1/2 data published in August. The Phase 2 portion of the trial involved 560 participants—160 participants aged 18-55 years (100 treatment, 60 control), 160 aged 56-69 years (120 treatment, 40 control), and 240 aged 70 years and older (200 treatment, 40 control)—and the participants were assigned to receive either 1 or 2 doses of the injection. Notably, the control group for this trial received a meningitis vaccine, as opposed to a true placebo, to reduce the differences in local reactions to the injection that could signal to patients or researchers which injection was used.
The researchers identified similar immune responses to this SARS-CoV-2 vaccine across all age groups, among those who received the second “boost dose” of the vaccine. At 14 days after receiving the boost dose, more than 99% of the participants exhibited neutralizing antibody immune response, and T-cell responses peaked at day 14 after the single dose of the vaccine. No serious adverse events were attributed to either vaccine, although minor adverse events were reported more often among younger individuals.
Over the course of the pandemic, pharmaceutical companies and governments have favored releasing clinical trial results via press releases, which provides information more rapidly than publishing in a peer-reviewed journal but does not allow additional scrutiny of the data that would increase confidence in the results. This article represents a continued effort to subject clinical trial data for SARS-CoV-2 vaccines to peer review following the initial press release. The researchers note that Phase 3 data “will be published elsewhere.”
PFIZER EUA
Earlier today, Pfizer and BioNTech announced that they are submitting Emergency Use Authorization (EUA) request to the US FDA for their SARS-CoV-2 vaccine candidate. The press release noted that the submission was based on the high vaccine efficacy rate (95%) found in the Phase 3 clinical trial. Their study provided evidence of requisite levels of safety and efficacy in individuals with and without prior SARS-CoV-2 infection. News media outlets are speculating that the FDA review process could take at least a few weeks and that an advisory committee is tentatively scheduled to meet in early December.
CHINA
Sinovac Biotech published results from the Phase 1/2 clinical trials for its SARS-CoV-2 vaccine candidate. The results, published in Lancet: Infectious Diseases, cover data from 743 study participants (143 from Phase 1 and 600 from Phase 2). The Phase 2 participants were divided into 3 study groups, 2 doses administered 14 days apart (240 participants), 2 doses administered 28 days apart (240), and placebo (120), and each group was split between a low-dose (6μg) and high-dose (6μg) vaccine. Neutralizing antibodies were detectable in at least 92% of the participants in all 4 treatment groups (14- and 28-day schedules and low- and high-dose vaccines), and participants receiving the 28-day schedule exhibited slightly higher seroconversion.
Some public health and vaccine experts have emphasized the need to see more data before jumping to any larger conclusions about the vaccine candidate. While the seroconversion data is encouraging, there are still no data available regarding the vaccine’s efficacy, like was announced recently for the Pfizer and Moderna vaccines. Additionally, these data correspond only to Phase 2 clinical trials, and Sinovac has not yet announced any data from larger Phase 3 trials. The Sinovac vaccine candidate received emergency use authorization from the Chinese government earlier this year, and it has reportedly been administered to hundreds of thousands of Chinese citizens. It is unconventional to start vaccine administration prior to obtaining finalized efficacy data, which is usually acquired in Phase 3 trials. Sinovac announced that it hopes to share results of its Phase 3 trials in December.
TREATMENTS
BAMLANIVIMAB On November 10, the US FDA issued and Emergency Use Authorization (EUA) for bamlanivimab, a monoclonal antibody produced by Eli Lilly, for the treatment of mild or moderate COVID-19 patients who are at “at high risk for progressing to severe COVID-19 and/or hospitalization.” The announcement received considerable attention as the first EUA issued for a monoclonal antibody treatment for COVID-19. Following the EUA, the US NIH’s COVID-19 Treatment Guidelines Panel issued a statement regarding the role of bamlanivimab in the clinical treatment of COVID-19 patients.
Based on a review of the available clinical trial and other data, the panel determined that “there are insufficient data to recommend either for or against the use of bamlanivimab” as a treatment for non-hospitalized COVID-19 patients. The panel also explicitly recommend that “bamlanivimab should not be considered the standard of care for the treatment of [COVID-19] patients” [emphasis in original]. The panel highlights the small sample size in clinical trials conducted to date and calls for additional research in order to better characterize the effects of bamlanivimab as well as identify the patients who are most likely to benefit. Considering the relatively limited supply, the panel recommends that clinicians prioritize patients who are at the highest risk for progressing to severe disease. This analysis helps put the EUA announcement in context and provides expert guidance regarding the use of the newly authorized drug.
REMDESIVIR The WHO “issued a conditional recommendation against the use of remdesivir in hospitalized [COVID-19] patients.” Based on the WHO’s analysis, the available data do not demonstrate that remdesivir “improves survival and other outcomes.” In particular, the recommendation cites a lack of evidence that remdesivir reduces “mortality, need for mechanical ventilation, [or] time to clinical improvement.” The recommendation is part of the WHO’s effort to develop guidance on clinical care for COVID-19 patients. The clinical care guidance is a living document, and it is updated as new data become available. Detailed information is also updated in the living clinical care document maintained by the journal BMJ. Early data from remdesivir trials were inconsistent, with benefit demonstrated in some trials but not others. Following promising evidence from some of these trials, the US FDA issued an EUA for remdesivir as a treatment for COVID-19, in the absence of other viable treatment options. Data from recent studies of remdesivir, however, have been less promising, and it appears that its clinical benefits may be minor.
In response to the WHO announcement, Gilead Sciences, manufacturer of the name-brand remdesivir product Veklury, issued a press release noting that the drug remains the standard of care for COVID-19 patients numerous countries, including the US. The statement also emphasizes the ACTT-1 clinical trial demonstrated a statistically significant improvement in the time to recovery among patients treated with remdesivir and calls attention to the fact that clinical trial data from the Solidarity Trial, which factored heavily into the WHO’s analysis, have not been published publicly or peer reviewed. Notably, preprint publication of some of the Solidarity Trial data is available, including data on remdesivir.
REINFECTION Researchers from the La Jolla Institute for Immunology published (preprint) results from a study on longer-term immunity against SARS-CoV-2 conferred by natural infection. The study evaluated 185 individuals with previous SARS-CoV-2 infection. All participants, and the majority experienced COVID-19 disease but were not hospitalized. Most of the participants provided a single blood sample between 6 and 240 days after symptom onset, with 41 collected at least 6 months after symptom onset. A subset of 38 participants provided multiple samples over a period of several months. The researchers found that antibodies against the spike protein of SARS-CoV-2 were relatively stable and memory B cells were abundant after 6 months, leading to optimism that immunity against the virus could mitigate the risk of severe COVID-19 disease for “many years.”
While this could hold true for the majority of people, there is growing evidence of SARS-CoV-2 reinfections, suggesting that immunity to the disease is complex and nuanced. According to a summary published by Science, reports of reinfections were identified as early as April, but it was months later, in late August, that a reinfection case was officially confirmed. Cases determined to be reinfections are defined as those with at least 2 positive PCR tests with at least 1 month without any symptoms in between the tests. Because there is a risk that the second test could be a false positive as a result of residual viral RNA in the body or because the virus was never fully cleared, researchers must compare genetic sequences from both specimens in order to determine if they are sufficiently different to indicate 2 separate infections. If genetic sequence data are not available for both specimens, it could prevent documentation as a reinfection. A positive note, however, is that the reinfections generally tend to be milder thus far compared to the original infection, although additional research is required to more fully characterize the factors contributing to reinfection and the associated disease severity.
VIRAL SHEDDING Researchers from the UK and Italy published a study in The Lancet that discusses viral load and viral shedding dynamics for multiple coronaviruses, including SARS-CoV-2. The analysis is based on a systematic review of studies published up through June 6, 2020. In total, the study included 79 studies conducted on SARS-CoV-2, covering more than 5,000 patients. The included studies addressed various aspects of viral load and viral shedding, including associations with disease severity and age as well as in pre-symptomatic patients and asymptomatic infections. Most of the studies (58 of 79) were conducted in China, but this is not necessarily surprising. Most of the data early in the pandemic came from China, which likely accounts for most of the studies that were able to complete peer review and finalize publication by early June.
Overall, the duration of viral shedding increased with age. While there was a positive association between age and shedding duration in the upper respiratory tract, the association was not significant in stool. There was no association with respect to sex. Viral load in the upper respiratory tract tended to be higher soon after infection, typically peaking around the time of symptom onset or within the first 3-5 days of illness, followed by a steady decline over the course of infection. Viral load in the lower respiratory tract peaked later, “in the second week of illness.” Viral shedding in stool was “erratic” by comparison, with peak viral loads detected at 1 week, 2-3 weeks, and 5-6 weeks, depending on the study.
With respect to disease severity, the duration of viral shedding tended to be longer in patients with more severe disease, although several studies did not find evidence of this association. Among studies that compared symptomatic and asymptomatic individuals, several reported lower viral loads in asymptomatic individuals but others did not. Five (5) of 6 studies that studied the duration of viral shedding, however, found shorter duration in asymptomatic individuals. Additionally, several studies attempted to culture live virus from patient specimens. While the timing and results varied between studies, none reported successfully culturing virus from respiratory specimens more than 9 days after the onset of symptoms, regardless of the viral load present in the specimens. All of these studies were able to culture virus within the first week of symptom onset.
Viral load and viral shedding do not necessarily correlate directly with transmissibility; however, these studies provide insight into the dynamics of SARS-CoV-2 infection with respect to different types of patients, clinical presentation, and disease severity. Based on the totality of the data, the researchers conclude that “patients with SARS-CoV-2 infection are likely to be most infectious in the first week of illness” and that “immediate isolation” is key to mitigating transmission risk. The researchers also indicate that the inability to culture live virus in respiratory specimens more than 9 days after symptom onset suggests that patient isolation could be ended at Day 10 after symptom onset in non-severe cases. Evidence that viral load peaks around the time of symptom onset also supports the theory that COVID-19 patients are highly contagious shortly before the onset of symptoms as well as early in the course of disease.
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