COVID-19 Situation Report
Editor: Alyson Browett, MPH

Contributors: Clint Haines, MS; Natasha Kaushal, MSPH; Amanda Kobokovich, MPH; Christina Potter, MSPH; Matthew Shearer, MPH; Marc Trotochaud, MSPH; and, Rachel A. Vahey, MHS.
WEBINAR Join us for a webinar, Lessons Learned Implementing a Testing Strategy for a Pandemic Wedding, to learn more about COVID-19 testing strategies for hosting large personal gatherings on April 19 at 2pm ET. With new COVID-19 variants, waning immunity, and low booster vaccination numbers, holding large personal events, like weddings, bar mitzvahs, and anniversary parties, can be complicated. Dr. Manoj Jain (Rollins School of Public Health) will discuss the four-pronged approach (communication, vaccination, masking, and testing) that helped his family safely plan and host a wedding during the pandemic. Register here
EPI UPDATE The WHO COVID-19 Dashboard reports 493.4 million cumulative cases and 6.17 million deaths worldwide as of April 7. The global weekly incidence decreased for the second consecutive week, down 14% from the previous week, and notably, all regions reported decreasing trends in weekly incidence last week. After a 1-week spike in reported global weekly mortality 2 weeks ago—46,479 deaths the week of March 21; +41% from the previous week—the trend is once again decreasing, down 42% from the previous week and -18% compared to the week of March 14. 

Global Vaccination
The WHO reported 11.3 billion cumulative vaccine doses administered globally as of April 5. A total of 5.06 billion individuals have received at least 1 dose, and 4.54 billion are fully vaccinated. Analysis from Our World in Data indicates that the overall trend in global daily vaccinations continues to decline, down from nearly 40 million doses per day in late December 2021 to 13.8 million on April 6, a decrease of nearly two-thirds over that period.* The trend continues to closely follow that in Asia. Our World in Data estimates that there are 5.09 billion vaccinated individuals worldwide (1+ dose; 64.7% of the global population) and 4.58 billion who are fully vaccinated (58.2% of the global population). A total of 1.71 billion booster doses have been administered globally.
*The average daily doses administered may exhibit a sharp decrease for the most recent data, particularly over the weekend, which indicates effects of reporting delays. In an effort to reflect the longer-term trends, the numbers reported here may not correspond to the most recent data.

The US surpassed 80 million cumulative cases on April 4.
1 case to 20 million: 343 days
20 to 40 million: 247 days
40 to 60 million: 126 days
60 to 80 million: 86 days

The US CDC is currently reporting 80.1 million cumulative cases of COVID-19 and 980,220 deaths. The decline in daily incidence tapered off at approximately 25-26,000 new cases per day from March 25-April 4, but the average jumped to 26,845 on April 5. Daily mortality continues to decline, down to 533 deaths per day on April 5, an 80% decline from the recent high in early February.* Notably, the average daily mortality is at its lowest level since August 2, 2021. At this pace, the US would surpass 1 million cumulative deaths in slightly more than 1 month; however, the decreasing trend is encouraging, and the timeline will likely be longer than this.
*Changes in state-level reporting may affect the accuracy of recently reported data, particularly over weekends. In an effort to reflect the longer-term trends, the numbers reported here may not correspond to the most recent dates.

US Vaccination
The US has administered 563 million cumulative doses of SARS-CoV-2 vaccines. Daily vaccinations have increased slightly over the past several days, with the average climbing from 154,000 on March 28 to 227,000 on March 31. Based on the timing of the increase, it is likely a result of the US FDA’s authorization of a second booster dose of the mRNA-based SARS-CoV-2 vaccines for certain individuals. A total of 256 million individuals have received at least 1 vaccine dose, which corresponds to 77.1% of the entire US population. Among adults, 88.5% have received at least 1 dose, as well as 27.4 million children under the age of 18. A total of 218 million individuals are fully vaccinated**, which corresponds to 65.7% of the total population. Approximately 75.6% of adults are fully vaccinated, as well as 22.9 million children under the age of 18. A total of 98.3 million individuals have received an additional or booster dose. This corresponds to 45.1% of fully vaccinated individuals, including 67.6% of fully vaccinated adults aged 65 years or older.
*Due to delays in reporting, estimates for the average daily doses administered are less accurate for the most recent several days. 
**Full original course of the vaccine, not including additional or booster doses.

ISRAELI FOURTH DOSE STUDY Researchers from Israel published findings from a study on the effectiveness of fourth doses of the Pfizer-BioNTech SARS-CoV-2 vaccine (ie, second booster dose). The study, published in the New England Journal of Medicine (NEJM), evaluated health records data from more than 1.2 million adults aged 60 years and older who were eligible for a fourth dose of the vaccine during Israel’s Omicron surge. Israel authorized fourth doses for several high-risk groups in January, including adults aged 60 years and older and healthcare workers.

The researchers compared the rate of SARS-CoV-2 infection and severe COVID-19 disease between individuals who received 4 doses of the vaccine and those who received 3 doses. The rate of severe COVID-19 among the 4-dose group at 4 weeks after the fourth dose was 3.5 times lower than the 3-dose group. Similarly the rate of infection in the 4-dose group was half of that among the 3-dose group. Protection against infection waned, however, with no significant increase in protection by week 8. The study period for severe disease was only 6 weeks, but the fourth dose’s increased effectiveness remained significant through that period and actually increased from a factor of 3.5 at week 4 to 4.3.

The study illustrates that additional booster doses can provide increased protection against infection and severe disease beyond the effect of the first booster dose; however, the effects may provide only moderate additional benefit and for a relatively short duration. The added protection against infection faded within 8 weeks, and the 6-week study period for severe disease does not provide evidence of prolonged protection. The study also does not compare the fourth dose to unvaccinated individuals or fully vaccinated individuals without a booster or for adults under the age of 60. So while a fourth dose provides a statistically significant benefit beyond the effect of the third dose, it is possible that the third dose provides sufficient protection and that the added benefit of an additional booster is relatively minimal and unnecessary. Many questions remain regarding the value and strategy regarding future booster doses for SARS-CoV-2 vaccines, and this study contributes analysis necessary for those debates.

FUTURE VACCINE STRATEGY US federal regulators and vaccine science experts met on April 6 to discuss the future of SARS-CoV-2 vaccination, including what a strategy and framework might look like. Last week, the US FDA authorized and the US CDC recommended that adults aged 50 years and older and individuals with certain kinds of immunocompromise can receive a fourth dose, or second booster, of an authorized mRNA vaccine. During this week’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), regulators were careful to say that the recent decision on boosters is a “stopgap measure” to protect these certain vulnerable groups until a more comprehensive booster plan can be considered. One framework being considered is based on the process used to update influenza vaccines. But presenters at the meeting underscored the challenges in predicting future SARS-CoV-2 variants, updating vaccine formulations, and collecting enough rigorous data in time to produce sufficient supplies.  

The committee did not hold a vote during this meeting but is expected to reconvene later this spring or early summer to consider updated booster formulations for this fall. In order to achieve this goal, manufacturers would need to begin collecting new data within the next few weeks. This is a tight timeline in order to meet a fall authorization deadline, but some manufacturers are hoping to soon submit data on reformulated vaccines. Pfizer has announced its intention of making new vaccine formulations that would potentially cover emerging SARS-CoV-2 variants and provide coverage on an annual schedule. The panel also discussed what information is still needed to help solidify future vaccine strategy, including consensus on correlates of immune protection from both antibodies and memory cells and vaccine efficacy level against severe disease. 

In Europe, the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMA) issued advice on a fourth vaccine dose, concluding there is not enough evidence yet to recommend the extra shots for the general population. However, both agencies agreed that data supports second boosters for people aged 80 and older in order to reduce the risk of severe disease.

US LONG COVID PLAN US President Joe Biden on April 5 directed government agencies to redouble their efforts to mitigate the long-term impacts of COVID-19, including making additional strides to research and treat post-acute sequelae of COVID-19 (PASC), commonly known as long COVID. The condition, which can last for weeks, months, or even years, is characterized by a variety of symptoms including brain fog, fatigue, shortness of breath, muscle weakness, depression and anxiety, and other symptoms. President Biden’s announcement follows criticism from patients and experts who say the federal government is not moving quickly enough to better define the condition, ascertain its prevalence, and learn more about who might be at increased risk of developing long COVID. 

The plan includes several components, including the creation of a new national council to coordinate interagency efforts on long COVID focused on improving care, enhancing outreach and education, and advancing research. Specific actions include accelerating the enrollment of 40,000 people in the ongoing US NIH RECOVER Initiative; publishing a report within 120 days detailing available federal agency services for people with long COVID, those experiencing COVID-related loss, and individuals with pandemic-related mental health and substance use problems, with a focus on “high-risk communities”; establishing “Centers of Excellence” and better referral and care models for people with long COVID; educating healthcare providers to help detect, understand, and improve care for long COVID; ensuring health insurance coverage for long COVID care; increasing awareness of long COVID as a potential cause of disability and updating relevant policy; and strengthening support for workers experiencing the condition. Some of the efforts are dependent upon funding contained in President Biden’s fiscal year 2023 budget request, which includes US$20 million for the development of long COVID clinics and US$25 million for the US CDC to boost its long COVID research efforts. Outcomes of US Congressional budget negotiations will not be known for months.

COVID-19 CASE DEFINITION The US daily COVID-19 incidence has declined more than 95% from its record high in January, at the height of the Omicron surge, and current hospitalizations are down nearly 93%. These decreasing trends signal decreases in community transmission, but this may not be the only factor. On March 29, the New Hampshire Department of Health and Human Services (NHDHHS) updated how it reports COVID-19 hospitalizations, with a new metric that only includes patients treated with remdesivir and/or dexamethasone, drugs typically reserved for severe patients. After the change, the current statewide hospitalizations reportedly fell to fewer than 10, down from 20-25 the previous week. The New Hampshire Hospital Association (NHHA) reports explicitly note that the “Treated for COVID-19” numbers are a subset of the total hospitalized COVID-19 patients. The NHHA includes additional data for “COVID-Recovering,” which includes hospitalized COVID-19 patients that no longer qualify under the state case definition, such as patients who are still hospitalized and receiving treatment for COVID-19-related conditions. On April 6, NHHA reported 51 “COVID-Recovering” patients statewide, compared to only 6 “Treated for COVID-19” patients.

The NHDHHS announcement argued that the new metric aligns with treatment guidelines issued by the US NIH and better reflects the current epidemiological situation by focusing on patients hospitalized with severe COVID-19 disease. Several other states are reporting similar metrics; however, they do so alongside the total number of hospitalized COVID-19 patients, whereas New Hampshire lists only the new metric. New Hampshire removed the previous hospitalization metric from its COVID-19 dashboard, and historical data are only available in archived form.

The new approach excludes both patients hospitalized for other conditions that happen to test positive for SARS-CoV-2 infection and patients hospitalized for mild or moderate COVID-19 who are not treated with the designated drugs. A representative from NHHA emphasized that the total number of hospitalized patients more accurately reflects the burden on local health systems, because COVID-19 patients that do not meet the new case definition are still occupying beds and consuming hospital resources. Additionally, patients hospitalized for other conditions may require additional resources (eg, separate rooms, infection prevention protocols) if they test positive for COVID-19, which places additional burden on hospitals.

Both metrics provide valuable information, but they serve different purposes. It is critical to understand the methods of classifying and reporting COVID-19 data as well as their intended purpose, because these factors have major effects on what the data mean and how they are interpreted.

IMF GLOBAL STRATEGY The International Monetary Fund (IMF), in partnership with the Wellcome Trust, Coalition for Epidemic Preparedness Innovations (CEPI), and the Global Fund, this week warned that the pandemic is not over and published a working paper calling for a new strategy to manage the long-term risks of COVID-19, including the uncertainty surrounding how the pandemic will evolve. The groups urged the international community to recognize that pandemic financing and preparedness not only helps individual countries prepare for infectious disease crises but also addresses systemic threats to the global economy. According to IMF projections, the pandemic will result in a cumulative output loss of US$13.8 trillion through 2024 and will leave lasting economic impacts in many countries. Additionally, global economic recovery will continue to be constrained without more equitable access to prevention and treatment tools and the development and implementation of policies addressing the pandemic’s consequences. 

The paper outlines 4 key policy implications of a long-term plan, including achieving equitable access to a comprehensive toolkit of treatment and prevention strategies such as diagnostics, vaccines, treatments, and healthcare system strengthening; monitoring viral evolution and responsively upgrading the toolkit; transitioning from an acute response to sustainable, balanced, and integrated health and social strategies that encompass COVID-19; and developing a cohesive risk-mitigation approach to future pandemic threats. To do this, the paper calls for US$15 billion in grants this year to fill the gap in the ACT Accelerator’s financing framework and US$10 billion annually moving forward to support pandemic preparedness and response (PPR) activities.

In related news, US Treasury Secretary Janet Yellen met with WHO Director-General Dr. Tedros Adhanom Ghebreyesus on April 5 to discuss ongoing COVID-19 pandemic responses and future efforts to strengthen global pandemic preparedness and financing. Secretary Yellen and Dr. Tedros agreed on the need to address these issues now, before global attention turns elsewhere. Secretary Yellen underscored the US commitment to working with the WHO, the World Bank, and G20 partners to develop a financial intermediary fund (FIF) on pandemic preparedness to be housed at the World Bank, and they agreed a FIF would serve as a vital component of the global architecture for pandemic preparedness. Additionally, Secretary Yellen and Dr. Tedros agreed on the importance of working toward the goal of vaccinating 70% of the world’s population this year, with Secretary Yellen emphasizing the US commitment to helping to achieve that goal. However, a compromise measure currently under consideration in the US Senate that would provide an additional US$10 billion for the COVID-19 response includes no additional funding for global vaccination efforts. Notably, the bill is stalled because of debate over immigration issues.

INFLAMMATORY RESPONSE Scientific evidence is mounting that SARS-CoV-2 infection can elicit massive inflammatory responses that contribute to severe COVID-19. In a study published April 6 in Nature, researchers describe how SARS-CoV-2 infection might cause these so-called cytokine storms, when the bloodstream is overrun with inflammatory proteins that then kill tissue and damage organs. The study demonstrates that SARS-CoV-2 can infect and replicate in certain types of white blood cells—macrophages in the lungs and monocytes in the blood—which, when infected, stimulate the release of inflammasomes, a type of molecule that triggers a rush of inflammatory responses. One of those responses is pyroptosis, a programmed cell death that leads infected cells to release even more inflammatory proteins and becomes a difficult process to treat. The study could help to explain why older adults or those with underlying health conditions such as obesity or diabetes are more vulnerable to severe COVID-19, as those people tend to already have some level of inflammation in the body. 

The results support the findings of another paper posted recently on bioRxiv, which is not yet peer-reviewed, that also found SARS-CoV-2 can infect and replicate in macrophages found in human lung cells and in a mouse model of the human immune system. Those infected macrophages also triggered the release of inflammasomes and died by pyroptosis. Typically, the virus uses ACE2 receptors to enter cells and replicate. However, monocytes and macrophages lack ACE2 receptors, so SARS-CoV-2 uses another cell-surface protein, Fcγ receptors, to enter cells, but only with the help of antibodies already attached to the Fcγ receptors. Notably, the antibodies in people who had received the Pfizer-BioNTech mRNA vaccine did not assist the virus in entering monocytes and therefore prevented subsequent inflammatory responses. Although additional research is needed to understand which antibodies facilitate viral uptake by monocytes, the finding is reassuring and could help researchers identify targets for future treatments.

IVERMECTIN The antiparasitic drug ivermectin showed no significant benefit in preventing hospitalization or prolonged emergency department visits due to COVID-19, according to the results of a large clinical trial published last week in the New England Journal of Medicine (NEJM). The study included nearly 1,360 COVID-19 patients in Brazil who were randomly assigned to receive either ivermectin or placebo within a week of developing symptoms, with some patients receiving a relatively high dose of the drug. The researchers underscored that the overall number of events in their study is larger than the number of all combined events in previous meta-analyses that provided inconsistent results. Despite ivermectin’s continued popularity as an alternative treatment, most experts agree that these findings provide conclusive evidence that the drug offers no treatment benefit for people with COVID-19 and question the value of additional studies examining the drug as a COVID-19 therapy.