Designing Advance Market Commitments for New Vaccines

Advance market commitments (AMCs) provide a mechanism to stimulate investment by suppliers of products to low-income countries. In an AMC, donors commit to a fund from which a specified subsidy is paid per unit purchased by low-income countries until the fund is exhausted, strengthening suppliers' incentives to invest in research, development, and capacity. Last decade saw the launch of a $1.5 billion pilot AMC to distribute pneumococcal vaccine to the developing world;in the current pandemic, variations on AMCs are being used to fund COVID-19 vaccines. This paper undertakes the first formal analysis of AMCs. We construct a model in which an altruistic donor negotiates on behalf of a low-income country with a vaccine supplier after the supplier has sunk investments. We use this model to explain the logic of an AMC-as a solution to a hold-up problem-and to analyze alternative design features under various economic conditions (cost uncertainty, supplier competition). A key finding is that optimal AMC design differs markedly depending on where the product is in its development cycle.

Optimal vaccine subsidies for endemic diseases.

In Goodkin-Gold et al. (2021), we analyzed optimal subsidies for a vaccine against an epidemic outbreak like Covid-19. This companion paper alters the underlying epidemiological model to suit endemic diseases requiring continuous vaccination of new cohorts-also suiting an epidemic like Covid-19 if, following Gans (2020), one assumes peaks are leveled by social distancing. We obtain qualitatively similar results: across market structures ranging from perfect competition to monopoly, the subsidy needed to induce first-best vaccination coverage on the private market is highest for moderately infectious diseases, which invite the most free riding; extremely infectious diseases drive more consumers to become vaccinated, attenuating externalities. Stylized calibrations to HIV, among other diseases, suggest that first-best subsidies can be exorbitantly high when suppliers have market power, rationalizing alternative policies observed in practice such as bulk purchases negotiated by the government on behalf of the consumers.

Testing fractional doses of COVID-19 vaccines.

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that, even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggests strong interest in these approaches.

Testing Fractional doses of COVID-19 Vaccines

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half- or even quarter-doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggest strong interest in these approaches.

Preparing for a Pandemic: Accelerating Vaccine Availability

Vaccinating the world’s population quickly in a pandemic has enormous health and economic benefits. We analyze the problem faced by governments in determining the scale and structure of procurement for vaccines. We analyze alternative approaches to procurement. We find that if the goal is to accelerate the vaccine delivery timetable, buyers should directly fund manufacturing capacity and shoulder most of the risk of failure, while maintaining some direct incentives for speed. We analyzed the optimal portfolio of vaccine investments for countries with different characteristics as well as the implications for international cooperation. Our analysis, considered in light of the experience of 2020, suggests lessons for future pandemics.

Optimal Vaccine Subsidies for Endemic and Epidemic Diseases

Vaccines exert a positive externality, reducing spread of disease from the consumer to others, providing a rationale for subsidies. We study how optimal subsidies vary with disease characteristics by integrating a standard epidemiological model into a vaccine market with rational economic agents. In the steady-state equilibrium for an endemic disease, across market structures ranging from competition to monopoly, the marginal externality and optimal subsidy are non-monotonic in disease infectiousness, peaking for diseases that spread quickly but not so quickly as to drive all consumers to become vaccinated. Motivated by the Covid-19 pandemic, we adapt the analysis to study a vaccine campaign introduced at a point in time against an emerging epidemic. While the nonmonotonic pattern of the optimal subsidy persists, new findings emerge. Universal vaccination with a perfectly effective vaccine becomes a viable firm strategy: the marginal consumer is still willing to pay since those infected before vaccine rollout remain a source of transmission. We derive a simple condition under which vaccination exhibits increasing social returns, providing an argument for concentrating a capacity-constrained campaign in few regions. We discuss a variety of extensions and calibrations of the results to vaccines and other mitigation measures targeting existing diseases.

Designing Advance Market Commitments for New Vaccines

Advance market commitments (AMCs) provide a mechanism to stimulate investment by suppliers of products to low-income countries. In an AMC, donors commit to a fund from which a specified subsidy is paid per unit purchased by low-income countries until the fund is exhausted, strengthening suppliers' incentives to invest in research, development, and capacity. Last decade saw the launch of a $1.5 billion pilot AMC to distribute pneumococcal vaccine to the developing world;in the current pandemic, variations on AMCs are being used to fund Covid-19 vaccines. This paper undertakes the first formal analysis of AMCs. We construct a model in which an altruistic donor negotiates on behalf of a low-income country with a vaccine supplier after the supplier has sunk investments. We use this model to explain the logic of an AMC—as a solution to a hold-up problem—and to analyze alternative design features under various economic conditions (cost uncertainty, supplier competition). A key finding is that optimal AMC design differs markedly depending on where the product is in its development cycle.

Could Vaccine Dose Stretching Reduce COVID-19 Deaths?

We argue that alternative COVID-19 vaccine dosing regimens could potentially dramatically accelerate global COVID-19 vaccination and reduce mortality, and that the costs of testing these regimens are dwarfed by their potential benefits. We first use the high correlation between neutralizing antibody response and efficacy against disease (Khoury et. al. 2021) to show that half or even quarter doses of some vaccines generate immune responses associated with high vaccine efficacy. We then use an SEIR model to estimate that under these efficacy levels, doubling or quadrupling the rate of vaccination by using fractional doses would dramatically reduce infections and mortality. Since the correlation between immune response and efficacy may not be fully predictive of efficacy with fractional doses, we then use the SEIR model to show that fractional dosing would substantially reduce infections and mortality over a wide range of plausible efficacy levels. Further immunogenicity studies for a range of vaccine and dose combinations could deliver outcomes in weeks and could be conducted with a few hundred healthy volunteers. National regulatory authorities could also decide to test efficacy of fractional dosing in the context of vaccination campaigns based on existing immune response data, as some did for delayed second doses. If efficacy turned out to be high, the approach could be implemented broadly, while if it turned out to be low, downside risk could be limited by administering full doses to those who had received fractional doses. The SEIR model also suggests that delaying second vaccine doses will likely have substantial mortality benefits for multiple, but not all, vaccine-variant combinations, underscoring the importance of ongoing surveillance. Finally, we find that for countries choosing between approved but lower efficacy vaccines available immediately and waiting for mRNA vaccines, using immediately available vaccines typically reduces mortality.

Return to Activity After SARS-CoV-2 Infection: Cardiac Clearance for Children and Adolescents.

CONTEXT: Sedentary behavior and inability to participate in organized physical activity has negatively affected the physical and mental health of children and adolescents; however, cardiac injury and associated risk for sudden cardiac death with return to activity remains a major concern. Guidelines have been proposed for return to activities; however, these fail to address the needs of younger children and those participating in more casual activities. Guidance is needed for primary care providers to facilitate safe return to everyday activity and sports and to help direct appropriate laboratory, electrocardiographic, and anatomical assessment. EVIDENCE ACQUISITION: Review of computerized databases of available literature on SARS-CoV-2 infection in children and postinfection sequelae, risk factors for sudden cardiac death, and previous return to play recommendations. STUDY DESIGN: Clinical guidelines based on available evidence and expert consensus. LEVEL OF EVIDENCE: Level 4. RESULTS: In this report, we review the literature on return to activity after SARS-CoV-2 infection and propose recommendations for cardiac clearance for children and adolescents. Though severe disease and cardiac injury is less common in children than in adults, it can occur. Several diagnostic modalities such as electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serologic testing may be useful in the cardiac evaluation of children after SARS-CoV-2 infection. CONCLUSION: Gradual return to activity is possible in most children and adolescents after SARS-CoV-2 infection and many of these patients can be cleared by their primary care providers. Providing education on surveillance for cardiopulmonary symptoms with return to sports can avoid unnecessary testing and delays in clearance.

Return to sports for adolescents and children after recovery from COVID-19

With the return to school, sporting events are resuming under the watchful eyes of local or state governments, which often seek guidance from medical organizations, sporting bodies, and the Centers for Disease Control and Prevention in formulating regulations. [...]effects on the cardiovascular system have been reported in children who are positive for SARS-CoV-2,14which may occur as part of multisystem inflammatory syndrome in children (MIS-C).5 9 Pediatricians also have seen many of these effects even in children with no overt symptoms, 10 the majority of which present weeks after the acute infection when the children would have completed quarantine and resumed sports.1112 Post COVID-19, the risk of developing serious complications such as MIS-C or cardiac complications such as myocarditis, arrhythmias, and heart failure is a cause of concern for the athlete, their parents, physicians, school boards, and sports licensing groups. The PCP should pay specific attention to the parts of the questionnaire that are pertinent to cardiac symptoms, such as episodes of chestpain, shortness of breath, exertional dizziness, excessive fatigue out of proportion for a viral upper respiratory infection, and new onset syncope and palpitations during the patient's infection or recovery. Pediatric patients who are hospitalized due to moderate-severe COVID-19 or MIS-C and/or have overt symptoms of myocarditis or heart failure should be treated according to existing guidelines of the American Heart Association and the American College of Cardiology for myocarditis.17 We note that COVID-19-related myocardial injury may be different from the typical viral myocarditis referred to in the guidelines, but in the absence of data, this approach is prudent.

Role of a Pediatric Cardiologist in the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected patients across all age groups, with a wide range of illness severity from asymptomatic carriers to severe multi-organ dysfunction and death. Although early reports have shown that younger age groups experience less severe disease than older adults, our understanding of this phenomenon is in continuous evolution. Recently, a severe multisystem inflammatory syndrome in children (MIS-C), with active or recent COVID-19 infection, has been increasingly reported. Children with MIS-C may demonstrate signs and symptoms of Kawasaki disease, but also have some distinct differences. These children have more frequent and severe gastrointestinal symptoms and are more likely to present with a shock-like presentation. Moreover, they often present with cardiovascular involvement including myocardial dysfunction, valvulitis, and coronary artery dilation or aneurysms. Here, we present a review of the literature and summary of our current understanding of cardiovascular involvement in children with COVID-19 or MIS-C and identifying the role of a pediatric cardiologist in caring for these patients.

Designing Pull Funding For A COVID-19 Vaccine.

A widely accessible vaccine is essential to mitigate the health and economic ravages of coronavirus disease 2019 (COVID-19). Without appropriate incentives and coordination, however, firms might not respond at sufficient speed or scale, and competition among countries for limited supply could drive up prices and undercut efficient allocation. Programs relying on "push" incentives (direct cost reimbursement) can be complicated by the funder's inability to observe firms' private cost information. To address these challenges, we propose a "pull" program that incentivizes late-stage development (Phase III trials and manufacturing) for COVID-19 vaccines by awarding advance purchase agreements to bidding firms. Using novel cost and demand data, we calculated the optimal size and number of awards. In baseline simulations, the optimal program induced the participation of virtually all ten viable vaccine candidates, spending an average of $110 billion to generate net benefits of $2.8 trillion-nearly double the net benefits generated by the free market.

Telehealth for Pediatric Cardiology Practitioners in the Time of COVID-19.

Due to the COVID-19 pandemic, there has been an increased interest in telehealth as a means of providing care for children by a pediatric cardiologist. In this article, we provide an overview of telehealth utilization as an extension of current pediatric cardiology practices and provide some insight into the rapid shift made to quickly implement these telehealth services into our everyday practices due to COVID-19 personal distancing requirements. Our panel will review helpful tips into the selection of appropriate patient populations and specific cardiac diagnoses for telehealth that put patient and family safety concerns first. Numerous practical considerations in conducting a telehealth visit must be taken into account to ensure optimal use of this technology. The use of adapted staffing and billing models and expanded means of remote monitoring will aid in the incorporation of telehealth into more widespread pediatric cardiology practice. Future directions to sustain this platform include the refinement of telehealth care strategies, defining best practices, including telehealth in the fellowship curriculum and continuing advocacy for technology.