The share of the population having received a first shot stands at 81% in Spain, 79% in Canada, 78% in Japan, 77% in Italy, 76% in France, 74% in Australia and Brazil, 73% in the UK, 69% in Germany, 66% in the US, 53% in India, and 39% in Russia. The daily pace of new doses administered (7DMA) increased to 28mn globally and 5mn in China and decreased to 0.9mn in the US, 0.9mn in the EU, and 5.6mn in India. The share of the population having received a booster shot stands at 45% in Israel, 31% in Chile, 15% in Turkey, 13% in the UK and Singapore, 6% in the US, 5% in France, 4% in Thailand and Brazil, 3% in Germany, Italy, and Spain, 2% in Canada, and 1% in Russia and Malaysia. Over the past week virus outbreaks have worsened in New Zealand, Norway, South Korea, the Czech Republic, Vietnam, Russia, Ukraine, Egypt, and Germany and improved in Singapore, the UK, Romania, and Australia (see chart). In developed markets, virus spread decreased in the UK and Canada, remained low in Japan and Spain, edged up in the US and France, and increased in Italy and Germany.
Total Moderna 2021 doses of 700-800M imply an average price/dose of ~$22 at the mid-point of guidance, similar to prior pricing. The short fall appears almost entirely to lower doses expected to be delivered in 2021 versus the prior 800M-1B guidance. I note in 2021 many doses that were shifted to early 2022 and prioritisation of deliveries to low-income countries through COVAX and African Union. MRNA expects deliveries of Spikevax in FY21 to be between 700mn-800mn doses at the 100µg dose level, with: i) longer delivery lead times for international shipments and exports that may shift deliveries to early 2022; ii) temporary impact from expansion of fill/finish capacity; and iii) ramp up of product release to market.
Fascinating perspective on Merck’s molnupiravir, just approved in the UK. For molnupiravir to be effective, it apparently must be taken within five days of symptom onset. This requires that an individual: recognize they have symptoms indicative of Covid-19, secure a Covid test, get the test results back in a timely manner, make an appointment with a doctor, get a prescription from the doctor for molnupiravir, buy the medication. This creates big issues. Data from Sutter Health show lower testing in outpatient settings for Black people in comparison to white, Asian, and Hispanic people, suggesting issues with access to getting Covid tests. Delays in getting a test, being informed of the result, and making an appointment with a doctor will all be harder among those with marginal or no insurance.
The rollout of earlier Covid-19 medications provides an illustrative example. Remdesivir, an intravenously administered antiviral that needs to be given early in the course of the disease and that can be administered only in the hospital, was given to Black cancer patients with Covid-19, a high-risk group, half as often as it was given to white patients. Its distribution was also uneven: safety-net public hospitals, which tend to serve racial and ethnic minorities as well as those with lower incomes, waited for supplies of remdesivir while smaller, private hospitals, which tend to serve higher-income populations, had earlier access. The evidence base for these new anti-Covid medications has also been inequitable: the majority of those in typical early studies were white. For individuals who are not sick enough to be hospitalized with Covid-19, using emergency departments or outpatient care clinics for access to molnupiravir is not the solution to these inequities. An emergency visit would incur large charges to the un- and underinsured and stress an already near-capacity hospital system. Already overburdened community-based clinics can often not accommodate urgent appointments, especially for those who are not already established patients at the clinic.
Even if a patient without insurance was able to navigate the first five steps listed earlier, buying the medication would be difficult, as a course of molnupiravir costs $700. Inequities in access to necessary medications are well documented, and while the country’s goal should be pharmacoequity — ensuring that all individuals have access to the medications they need — we are far from accomplishing it. The cost would escalate quickly if Covid-19 spread to family members, presenting some families with the choice between improving their odds against Covid-19 and incurring debt or bankruptcy. The federal government could provide the medication for free, as it has done with monoclonal antibody therapy, and has in fact already ordered 1.7 million courses of molnupiravir. But here, too, there are inequities between racial/ethnic groups, with white patients being more likely to get monoclonal antibody infusions. Many of those who receive monoclonal antibodies are referred by their primary doctor to an emergency department or an infusion centre, which limits access to this therapy to those who have primary care doctors. So simply eliminating cost won’t fix the problem. Removing one barrier to treatment is inadequate; all must be removed. Throughout the pandemic, the U.S. has been caught in endless loops of compounding inequities. With every new resource, though, we have the opportunity to recognise them earlier and do better moving forward:
Elsewhere, the vaccination status differs widely among Asia’s countries. Countries such as Singapore, South Korea, Malaysia, Japan and China have vaccinated higher proportion of population i.e. 74-84%, whereas countries such as Philippines, Indonesia, India, Thailand & Hong Kong have vaccinated 25-59% of their total population. For Singapore, as the vaccination status has reached 84% and the country is now opening up its international borders quarantine free. It started its booster shot programme from late September and now has inoculated 16% of the total population with booster dose. This is Asia’s daily infection curve per 100K population:
China’s vaccination speed rose up to 3.1m/day last week (vs 1.9m doses/day two weeks ago). Broadly speaking, more than 20 out of 32 provinces/municipalities have officially kickstarted the booster shot program. In principle, all adult people who have received two doses more than six months ago are eligible to be inoculated with a booster shot whereas vulnerable group and frontline workers in high infectious risk regions are still prioritized. Thus, near-term vaccination speed is likely to pick up in the coming weeks considering the ample supply of vaccine doses and the fact that mass inoculation in tier 1 cities was concentrated in second quarter. China has registered ~2,275 million vaccine doses as of now, which fully covers the whole population of 1,439 mn. The Chinese government has updated the latest number of fully vaccinated people (i.e. 74% of total population as of 29 Oct), laying a solid foundation for reopening plan in autumn as prerequisite of border reopening is that vaccination at least reaches the threshold at 80%-85%. Based on current vaccination pace, I think the target is likely to be achieved by year end.
Elsewhere, one further positive sign is that average daily new cases continued declining in India for the third week after rising for two consecutive weeks (16k/d, -18% w/w). The estimated R0 stayed below 1.0 (0.94, -0.07 w/w) in the past week. I think that recent curve pressure looks to reflect India’s large scale economic re-opening. Unfortunately, the daily new mortality pick up in past week to 506/d (+83% w/w) implies that the health capacity is under certain pressure and many severe cases haven’t been treated in a timely/appropriate way following an infection rebound in last week. I note 6 of 7 infections in Africa are undetected:
With the global expansion of the Delta (B.1.617.2) variant, researchers conducted a matched test-negative case–control study to assess the real-world effectiveness of COVID-19 messenger RNA vaccines against infection with Delta in Qatar’s population. BNT162b2 effectiveness against any, symptomatic or asymptomatic, Delta infection was 45.3% (95% CI, 22.0–61.6%) ≥14 d after the first vaccine dose, but only 51.9% (95% CI, 47.0–56.4%) ≥14 d after the second dose, with 50% of fully vaccinated individuals receiving their second dose before 11 May 2021. Corresponding mRNA-1273 effectiveness ≥14 d after the first or second dose was 73.7% (95% CI, 58.1–83.5%) and 73.1% (95% CI, 67.5–77.8%), respectively. Notably, effectiveness against Delta-induced severe, critical or fatal disease was 93.4% (95% CI, 85.4–97.0%) for BNT162b2 and 96.1% (95% CI, 71.6–99.5%) for mRNA-1273 ≥ 14 d after the second dose. Their findings show robust effectiveness for both BNT162b2 and mRNA-1273 in preventing Delta hospitalization and death in Qatar’s population, despite lower effectiveness in preventing infection, particularly for the BNT162b2 vaccine.
The effectiveness of the BNT162b2 vaccine in preventing disease and reducing viral loads of breakthrough infections (BTIs) has been decreasing, concomitantly with the rise of the Delta variant. However, it is unclear whether the observed decreased effectiveness of the vaccine in reducing viral loads is inherent to the Delta variant or is dependent on time from immunization. By analysing viral loads of over 16,000 infections during the current, Delta-variant-dominated pandemic wave in Israel, we found that BTIs in recently fully vaccinated individuals have lower viral loads than infections in unvaccinated individuals. However, this effect starts to decline 2 months after vaccination and ultimately vanishes 6 months or longer after vaccination. Notably, they found that the effect of BNT162b2 on reducing BTI viral loads is restored after a booster dose. These results suggest that BNT162b2 might decrease the infectiousness of BTIs even with the Delta variant, and that, although this protective effect declines with time, it can be restored, at least temporarily, with a third, booster, vaccine dose.
Now that these vaccines are widely available, the next important step is to assess real-world vaccine effectiveness (VE), especially against evolving variants of the virus. Comparing VE provides useful data for decision-makers to adjust public health policy based on the vaccines’ performance, and it also can be considered a valuable source for gaining public trust. Compared with the messenger RNA (mRNA)–based vaccines, the Ad26.COV2.S vaccine (Johnson & Johnson) has been administered less often; concurrently, there are fewer data on VE for this vaccine. Researchers now provide valuable data for the real-world effectiveness of the Ad26.COV2.S vaccine in an observational, retrospective, comparative effectiveness research study. This study consisted of 8889 vaccinated and 88,898 unvaccinated individuals, with matching based on age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 PCR tests. The authors found that the VE of the Ad26.COV2.S vaccine was 73.6%, which is in accordance with the effectiveness of 66.9% reported in the phase 3 clinical trial of this vaccine. In addition, the study shows that the Ad26.COV2.S vaccine reduces the risk of hospitalization and intensive care unit admission:
Comment on this: the emergence of new variants of SARS-CoV-2 has raised concerns about immune evasion and reduced VE of vaccines that are developed based on the Wuhan strain. The study here is part of a growing body of work surrounding humoral responses to a single dose of the Ad26.COV2.S vaccine and VE. Several studies have showed that the recipients of the Ad26.COV2.S vaccine have lower neutralization activity against virus variants. In terms of VE, 2 studies have shown that the effectiveness of the Ad26.COV2.S vaccine is stable over time (before and after the emergence of the Delta variant), with a moderate decrease in effectiveness for individuals older than 75 years. The emergence of the Delta variant occurred in the final weeks of the study; thus, there were not enough cases to determine VE against this variant.
What is becoming more clear with time is that the single-dose regimen of the Ad26.COV2.S vaccine seems to be inferior to the mRNA-based vaccines in terms of VE. Data from the original clinical trials point to a VE of 66.9% with the Ad26.COV2.S vaccine, 95% with the BNT162b2 vaccine (Pfizer/BioNTech), and 94.1% with the mRNA-1273 vaccine (Moderna). Although the definitions and methods of these studies were different, the same trend was noted in 2 studies by the same group, 1 of which is the study here. Based on the second study by the same group, the VE against infection is 86.1% with the BNT162b2 vaccine and 93.3% with the mRNA-1273 vaccine, which is significantly higher than the 73.6% real-word effectiveness of the Ad26.COV2.S reported here. Regarding VE against the Delta variant, a recent study by the CDC shows that VE was 95% with the mRNA-1273 vaccine, 60% with the BNT162b2 vaccine, and 60% with the Ad26.COV2.S vaccine. Based on the recent findings here as well as the growing body of literature, it appears that the single-dose Ad26.COV2.S vaccine, although providing protection against infection and serious disease in most recipients, still has room for improvement. This may ultimately come in the form of a second dose of the same vaccine, as reported recently (increasing VE to 94%, per the manufacturer), or potentially by boosting the Ad26.COV2.S vaccine with another vaccine (mRNA or protein based).
Next, in 1800 health care workers at Hopkins with prior SARS-CoV-2 infection followed by 2 doses of mRNA vaccine (3 independent exposures to spike antigen) developed higher spike antibody measurements than individuals with vaccination alone. Consistent with work comparing extended vaccine dosing intervals, the study showed that a longer interval between infection and first vaccine dose may enhance the antibody response.
Next, cannabis use among pregnant women is common and has increased in recent years in the US, from an estimated 3.4% in 2002 to 7.0% in 2017. Pregnant women report using cannabis to relieve stress and anxiety, and prenatal cannabis use may have risen during the COVID-19 pandemic as pregnant women faced general and pregnancy-specific COVID-related stressors (eg. social isolation, financial and psychosocial distress, increased burden of childcare, changes in prenatal care, and concerns about heightened risks of COVID-19). Considered an essential business in California, cannabis retailers remained open during the pandemic with record sales in 2020. A group used data from Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system with universal screening for prenatal cannabis use to test the hypothesis that rates of prenatal cannabis use increased during the COVID-19 pandemic. They found rates of biochemically verified prenatal cannabis use increased significantly during the COVID-19 pandemic among pregnant women in Northern California. Results are consistent with the rise in cannabis sales seen in California during the same period. When the toll of the COVID-19 pandemic begins to fade and restrictions are lifted, it is unknown whether pandemic-related increases in rates of cannabis use during pregnancy will reverse or remain elevated. Continued monitoring of trends is critical as the pandemic continues to evolve.
Researchers asked what is the association of maternal SARS-CoV-2 infection with immune response in offspring in the first 2 months of life? In this cohort study of 21 mothers who tested positive for SARS-CoV-2 at delivery and their 22 newborns, there was 1 case of potential mother-infant vertical virus transmission and 1 case of horizontal virus transmission. Infants who received breastmilk during the first 2 months of life had significantly higher spike-specific salivary IgA antibody levels compared with formula-fed infants, and IgA spike immune complexes were detected in breastmilk. Findings suggest that maternal protection goes beyond passive immunity, with immune complexes in breastmilk stimulating the active development of the neonatal immune system:
A study found a considerable decrease in the average number of weekly insulin prescription fills during the COVID-19 pandemic. Reduced contact with prescribing clinicians during the pandemic, rationing, previous stockpiling, or loss of insurance could explain the decline. The lack of substantial decline in pediatric patients’ prescriptions can be explained by the fact that insulin use in pediatrics is more likely for type 1 diabetes:
The eagerly awaited onset of vaccination programs against COVID-19, along with people’s urge to return to “normal life,” has prompted concerns that individuals who were vaccinated would reduce their protective behaviours faster than recommended. Whereas worries about risk compensation have proven unfounded in some preventive medicine contexts (eg. human papillomavirus vaccination), signs of riskier conduct among the treated have appeared in others (eg. individuals who use HIV preexposure prophylaxis). Based on representative samples of 12 countries in various stages of immunization programs, this study compared the self-reported protective behaviours of individuals who had received 0, 1, or 2 COVID-19 vaccine doses. Despite occasional significant results, all of small magnitude, overall, this cross-sectional study found no substantial reduction in physical distancing or mask use associated with receipt of COVID-19 vaccine doses. This suggests that until early June, people generally did not engage in concerning levels of risk compensation as they acquired immunity. There was no discontinuity in behaviour soon after US President Joe Biden announced that US adults who had been fully vaccinated need not wear masks or physically distance:
Recent reports suggest a possible association between Ad26.COV2.S (Johnson & Johnson) COVID-19 vaccination and cerebral venous sinus thrombosis (CVST). Estimates of postvaccination CVST risk require accurate age- and sex-specific pre-pandemic CVST incidence rates; however, reported rates vary widely. They found that the CVST incidence rate 15 days after Ad26.COV2.S vaccination was significantly higher than the pre-pandemic rate. However, the higher rate of this rare adverse effect must be considered in the context of the effectiveness of the vaccine in preventing COVID-19 (absolute reduction of severe or critical COVID-19 of 940 per 100 000 PY).Most CVST events occurred within 15 days after vaccination, which is likely the highest at-risk period. The postvaccination CVST rate among females was higher than the pre-pandemic rate among females. The highest risk was among women aged 30 to 49 years, but the absolute CVST risk was still low in this group (up to 29.5 per 100 000 PY among women aged 40-49 years):
Researchers asked does 2 units of ABO-compatible, high-titer convalescent plasma, administered to critically ill patients with COVID-19, improve organ support–free days up to day 21 (a composite end point of in-hospital mortality and the duration of intensive care unit–based respiratory or cardiovascular support)? This international bayesian randomized clinical trial that included 2011 participants treated with 2 units of high-titer convalescent plasma, compared with no convalescent plasma, resulted in a posterior probability of futility of 99.4% for the primary outcome of organ support–free days up to day 21. Among critically ill adults with confirmed COVID-19, treatment with convalescent plasma had a low likelihood of providing improvement in organ support–free days:
Next, among symptomatic but clinically stable outpatients with COVID-19, does adding antithrombotic therapy, compared with placebo, reduce major cardiopulmonary adverse outcomes over a 45-day treatment period? This randomized trial of 657 symptomatic outpatients with COVID-19 conducted in the US was stopped early because of an unanticipated low event rate. Among randomized participants who initiated trial treatment with aspirin (81 mg once daily), apixaban (2.5 mg twice daily), apixaban (5.0 mg twice daily), or placebo, the rates of an adjudicated composite outcome (all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause) after 45 days were 0.0%, 0.7%, 1.4%, and 0.0%, respectively; there were no significant differences between the active groups and the placebo group. These data do not support the use of aspirin or apixaban in the outpatient setting to reduce the major adverse cardiovascular or pulmonary consequences associated with symptomatic but clinically stable SARS-CoV-2 infection:
Next, after vaccination, the occurrence of erythematous and indurated skin reactions has been reported at an average of 8 days after the first or second injection. The identification of such hypersensitivity responses has been a focus of study for many years by researchers investigating various systems. Such reactions to mRNA vaccines strongly resemble the primary first-dose flare and secondary skin-test responses that we reported 45 years ago in volunteers who were injected with foreign proteins. At that time, some have noted that the studied reactions were similar to those described as Jones–Mote responses (JMR) to rabbit serum proteins by Dr. T. Duckett Jones and a medical student, John Mote, in 1934 in the NEJM. In their 1976 case report, the antigen that was used was the copper-carrying (and thus blue) protein called keyhole limpet hemocyanin (KLH), which is found in a Pacific Ocean marine gastropod. They identified the cutaneous JMR to KLH as a strong example of cutaneous basophil hypersensitivity (CBH). This delayed reaction was caused by a T-cell response that is rich in basophils to remnants of an intradermal skin-test injection of a strong foreign antigen, as described by Ann and Hal Dvorak in 1970. The study volunteers who had these JMR and CBH reactions were 20 White Yale medical students.
It seems that the rare cutaneous hypersensitivity reactions among recipients of mRNA vaccines are responses to the translated spike protein of the SARS-CoV-2. JMR and CBH reactions to the KLH protein in their skin-immunized volunteers were highly antigen-specific in vivo T-cell–dependent responses to residual antigen that was left at the local site from the first injection, to which the host had a primary immune T-cell JMR. Then similar reactions were elicited to secondary skin-test exposures. Such reactions also include antigen-specific T-cell proliferation with distinct kinetics, reactions that now are ripe for more modern molecular analysis.
Recognition that responses to the mRNA Covid-19 vaccines resemble JMR and CBH reactions may lead to skin testing in patients and to other related studies to better understand SARS-CoV-2 infections. Perhaps so-called “long Covid” has a similar pathogenesis and could respond to treatments appropriate to JMR and CBH reactions. An example may be the improvement that was seen in patients with long Covid who were treated with combined antihistamines, since the source of histamine may be the basophils:
Of the pandemics faced in the 20th century, none were more severe than the influenza A/PR/8/34 (H1N1) outbreak of 1918, the so-called Spanish influenza. Emerging during World War I, this pandemic is estimated to have infected nearly one-third of the global population and killed approximately 50 million people, including 675,000 people in the US. While the pandemic was brief, some individuals experienced reaching effects. Women infected with the flu during pregnancy had children found to have higher rates of heart disease, kidney disease, and diabetes throughout their life course. The implications of such findings hold relevance today, as the novel coronavirus SARS-CoV-2 has spread throughout the world. Given the effects observed in the 1918 pandemic and reported birth outcomes related to maternal COVID-19 infection, it is prudent to use the lessons and epidemiology of the 1918 pandemic to inform practice and follow-up of potential long-term health effects associated with maternal COVID-19 infection.
The 1918 influenza was unusual in the vigour with which it affected young adults, but other populations were not spared, including fetuses in utero. Birth rates declined along with an increased rate in stillbirths, but carrying a pregnancy to birth did not ensure that born children avoided the effects of influenza. Rates of congenital malformation and premature birth increased during all waves of the pandemic, contributing to increased infant mortality rates during the spring 1919 wave. Premature birth from any cause is a risk for associated conditions, such as kidney or heart disease, later in life, compounded by any risk that may be associated with in utero exposure to maternal infection.
Like the influenza of 1918, maternal COVID-19 infection during pregnancy has been associated with increased risk of neonatal and perinatal complications. Notably, premature birth rates in mothers infected with COVID-19 have been observed to be significantly elevated from their pre–COVID-19 rate, and low birth weight in children of mothers infected with COVID-19 has also been observed, although little evidence has supported that neonates are at major risk of direct harm through processes like vertical transmission.
However, such outcomes could have long-term effects even in the absence of direct neonatal infection. The Barker hypothesis postulates that interruptions in normal in utero development can have lasting health effects specific to the organ systems developing at that time. For example, the heart develops during the first trimester, and as such, children of mothers infected with a disease during this time may bear a higher risk of cardiovascular disease later in life. Conversely, children of mothers infected with a disease in their third trimester, when the kidney is still maturing, may show an increased risk of chronic kidney disease and lower nephron number. The risk to the kidneys is compounded by the higher observed prevalence of preterm birth, as postnatal maturation does not compensate for the lost gestational time, increasing the risk for kidney complications later in life, such as hypertension and chronic kidney disease. There are several proposed mechanisms for this disruption of development, including reduced supply of both micronutrients and macronutrients during maternal infection, increased cytokine secretion, and an increase in glucocorticoids in response to maternal infection.
The potential for negative long-term outcomes is not theoretical. In a life-course study of individuals exposed in utero to influenza during the 1918 pandemic, Garthwaite1 found significant increases in heart disease, diabetes, and kidney disease compared with the general population. In a similar study, Almond and Mazumder7 saw comparable increases in negative health outcomes, including significant increases in heart disease, kidney disease, stomach disease, and hypertension, for individuals exposed in utero during the 1918 pandemic. Both studies describe a time-dependent relationship between prenatal exposures and risk of negative health outcomes later in life, with births in May 1919 having the highest rates of diabetes, births in November 1918 having the highest rates of kidney disease, and births between December 1918 and May 1919 having the highest rates of heart disease. Such a relationship aligns with what may be expected from the Barker hypothesis, that maturing organ systems at the time of maternal infection will face higher risk of deleterious outcomes later in life.
While birth outcomes face increased risk from maternal COVID-19 infection, conclusions drawn from life-course studies from the 1918 pandemic suggest that risk of COVID-19 exposure in utero may have life-course effects. Thus, a life-course study of this population offers an opportunity to gather information to improve their outcomes and contribute to a wider understanding of long-term pandemic effects. Various methodologies are available for conducting life-course studies, including collecting data from large-scale surveys, such as the National Health Institute Survey. Surveys can collect substantial health information at one time but are susceptible to recall and self-reporting biases. Focused tracking of patients with health outcomes examined at regular intervals by research personnel allows for a more robust examination of outcomes, including severity and timing. Following a prospective cohort of maternal-child dyads over time offers an opportunity to study the effect of maternal COVID-19 infection on social determinants of health, growth and development, milestones, and biomarkers, such as blood glucose, lipids, viral antibodies, and inflammatory markers. However, intensive follow-up is considerably more resource intensive and risks losing participants to follow-up; methods to mitigate such risks are needed for any long-term study. Some registries, such as the Pregnancy Coronavirus Outcomes (PRIORITY) Registry and MotherToBaby Registry, are already studying short-term outcomes in infants born to mothers who have had COVID-19, including the effect on breastfeeding. This is invaluable research and provides a framework for which longer-term study can be initiated to investigate life-course effects. However, any long-term study faces challenges from the large number of patients with unrecognized COVID-19 infection. The presence of such patients must be considered in recruiting patient cohorts. Furthermore, as the COVID-19 pandemic has not equally affected all populations, any study should be undertaken with consideration toward the particular health risks faced by these populations where COVID-19 has been more prevalent.
Maternal COVID-19 infection has resulted in elevated rates of preterm birth and low birth weight. However, it has yet to be determined if children born to mothers infected with COVID-19 face deleterious long-term health outcomes. The prevalence of perinatal complications already observed combined with observations from life-course studies in past pandemics suggests that these children face potential risk of long-term health outcomes and should be followed up with for observation of those outcomes. The rise in perinatal complications, such as prematurity in children born to mothers infected with COVID-19, not only poses a risk for negative long-term outcomes by itself—particularly to late-maturing organs, such as the kidneys—but also indicates that in utero exposure could have broader implications than are initially apparent. Just as children born during the 1918 pandemic faced differing risks of future negative outcomes depending on when in utero they faced the peaks of the pandemic, the timing of maternal COVID-19 infection may too present higher risk for certain outcomes in these children. As such, these children could be observed for development of negative health outcomes. Registries like the PRIORITY and MotherToBaby registries are already studying short-term effects, but such large-scale databases are needed to examine effects in the longer term as well to determine if these children face a higher relative risk than their counterparts born at a similar time to mothers who were not infected with COVID-19.
The COVID-19 pandemic has immensely been challenging from a public health perspective. The magnitude of the global threat from this virus was underestimated early on by many health authorities as attempts at containment and mitigation were made. As it became clear that the virus would become an established threat, achieving a balanced portfolio of antiviral agents, monoclonal antibodies and vaccines was challenging to accomplish, given competing priorities and limited resources. In addition, manufacturing capacity across the globe was not sufficient to immediately rise to the scale of production necessary for the diagnostic tools, therapeutic agents, vaccines and personal protective equipment needed to combat the pandemic. Even though these issues have now been at least partially addressed, the global deployment of vaccines that aim to bring the outbreak under control has been complicated by political and social media disinformation campaigns that work against the public health.
One positive consequence of the ongoing pandemic for the public has been a heightened external awareness of the work of regulators and the innovative regulatory pathways that can be used to facilitate the availability of crucial medical products in an emergency. There has been some apprehension about the pace of the development of medical products during the pandemic, with some voicing concerns regarding the investigational nature of vaccines and other products that were made available under Emergency Use Authorization in the United States. Therefore, it has been critical to ensure that the development, review and authorization and approval process is as open and transparent as possible. This has included: providing clear standards for product development and review in regulatory guidance documents; making review documents public; holding open, easily accessible advisory committee meetings; and having senior agency staff speak to the public whenever possible about the evidence and decision making regarding COVID-19 diagnostics, therapeutic agents and vaccines.
Throughout the pandemic, within public health agencies such as the FDA, regulators have had to deal with the evaluation of unprecedented amounts of emerging scientific data and a deluge of product submissions, all under time pressures and a public health need that is unprecedented in our lifetimes. While this has strained regulatory systems, it has also led to a search for efficiencies across the spectrum of product development. The urgency to expedite the development of critical devices, therapeutic agents and vaccines led the agency to initiate conversations with product developers very early on during the product development lifecycle, and these frequent conversations often continued during clinical trials through authorization or approval. As the pandemic progressed, this informational program for therapeutic drugs and biological agents became known as the Coronavirus Treatment Acceleration Program. Although sponsors were not obligated to take the advice provided, many did so, and thereby took advantage of the agency’s expert knowledge in chemistry, manufacturing and controls, as well as in both conventional and innovative clinical trial design.
Global regulators have interacted to identify and evaluate potential safety signals, such as Guillain-Barré syndrome and myocarditis, arising after the deployment of COVID-19 vaccines. Greater regulatory collaboration and convergence would help to prepare for the inevitable next pandemic. Diagnostic tests, drugs and vaccines that ultimately need to be deployed globally could be developed according to unified expectations. This would allow product developers to generate the data necessary for global deployment just once, and thereby avoid the time-consuming rework that is currently necessary to meet the specific regulatory requirements of a multitude of different regulatory jurisdictions. Major regulators across different countries could also agree upon standardized formats for emergency access, and mutual recognition agreements could allow trusted regulatory partners to share the burden of regulatory review. These actions would simplify and expedite critical decision-making, which would in turn speed up access to essential, newly developed diagnostics, drugs and vaccines.
The current breakneck pace of regulatory work has been essential to reduce the burden of disease due to COVID-19, but this intensity of work cannot continue indefinitely. Refocusing resources on COVID-19 has come at the cost of delaying the development of other crucial medical products. For example, in the United States, our ability to provide timely feedback to developers of gene therapies has been impaired. As the world slowly moves into the post-pandemic period, regulators will need to pick and choose those aspects of regulatory process enhancements that are maintained, those that return to their pre-pandemic status, and those that should be implemented to help address the next global public health crisis better.
Choosing wisely to retain the most meaningful regulatory processes will be important to best meet the needs of industry and regulators, while maximally benefiting the public health. Increasing international convergence of regulatory requirements and continuing the enhanced dialogue between product developers and regulators are both useful lessons from COVID-19 that could be further built upon. By maintaining or amplifying the best practices that have been developed over the past two years, regulators, industry and the public can derive something of benefit from this terrible pandemic:
Prof. Justin Stebbing