Editor’s note:Ask the Expert is a column aimed at providing pediatricians information on pressing topics related to COVID-19. Email your questions to ahegland@aap.org.
Vaccine development for any infectious disease is a slow and arduous project. It generally requires more than 10 years to produce a licensed product and often costs more than $500 million. For a novel virus that is poorly understood such as SARS CoV-2, the process is particularly complex. However, the need for a safe and effective vaccine is indisputable.
Immunity to the virus that causes COVID-19 disease will be acquired in one of two ways: from a vaccine or from infection. Most people will prefer to acquire immunity to this potentially severe disease from vaccination.
Challenges in conducting clinical trials
The problems with vaccine development are substantial. Multiple vaccine platforms are in development, and clinical trials should not compete for subjects. Therefore, enrollment in a clinical trial with different candidate vaccines should be centralized.
Conducting a randomized clinical trial during a pandemic will be difficult because the location of disease outbreaks may be difficult to predict.
Vaccine trials will be conducted by different manufacturers, and the endpoints of clinical trials should be harmonized as much as possible so that relative efficacy can be determined clearly. Ideally, a central investigational review board will oversee many candidate vaccine trials.
Defining effectiveness
What will be the definition of an effective vaccine? Should reduction in mortality be the threshold, or should it be reduction in severe disease (hospitalization) or prevention of infection? What degree of prevention will be acceptable — a 50% reduction, a 75% reduction, a 90% reduction relative to placebo recipients?
Will a vaccinated person still be able to spread the wild type virus to susceptible contacts (as happens with recipients of the killed polio virus vaccine)? Different populations (such as children vs. adults) may respond differently to different vaccines and may require separate endpoints to define a successful vaccine. Can the candidate vaccine be co-administered with existing vaccines?
With high morbidity and mortality rates, certain populations may be reluctant to participate in randomized trials, especially after one vaccine is shown to have some degree of efficacy and is available.
What dose will be evaluated in a new vaccine? Will a vaccine adjuvant be necessary to stimulate a protective antibody concentration? Which adjuvant? What will the duration of immunity be? Will immunity last a season, a year or longer? Will booster doses be necessary? Immunity from infection by conventional coronavirus is not sustained and infection recurs.
At the present time, the serologic correlate of protection is not known. What is the role of T cell function in preventing infection? Once a specific antibody concentration is known to be protective, demonstration of seroconversion may replace the need for efficacy trials.
Vaccine safety
Safety is paramount. Immune enhancement of disease has been encountered with earlier vaccines, such as the killed measles vaccine and the formalin inactivated respiratory syncytial virus vaccine. The recently licensed dengue vaccine saves many lives around the globe. But among seronegative vaccinated children, there is a small increase in risk of serious infection relative to seronegative placebo recipients. Multisystem inflammatory syndrome in children appears to be a cytokine storm stimulated by specific viral antigens in genetically predisposed children. Thoughtful selection of antigen(s) included in a vaccine is critical.
Thorough assessment of a candidate vaccine’s safety requires sufficiently long follow-up to address delayed untoward reactions. How long will that be? How many subjects must be evaluated before a vaccine is deemed safe. Perhaps 20,000 subjects who receive a candidate vaccine or placebo will be sufficient. But that is unlikely to detect less common adverse events.
Manufacturing and distribution challenges
Once a successful vaccine is demonstrated, manufacture and distribution will need to be addressed. Millions of vaccine doses will be required for each country, and manufacturing capacity will be stretched.
The world population is nearly 7.7 billion people, and equity will demand access for all people. Fair global distribution of the vaccine is essential. Who will receive the initial doses as a vaccine becomes available?
Cost should not be permitted to impact access to the vaccine, but a pharmaceutical company still must be able to recoup development costs and derive profit from a successful vaccine.
Although unlikely, the global pandemic might end before a vaccine is available. This happened with SARS-CoV-1 virus. The last known cases were in 2004.
The global need for a vaccine in many geographic areas justifies the efforts by different vaccine manufacturers. While it is unlikely that more than a few vaccines will be safe and effective, manufacture and distribution of vaccines will require unprecedented cooperation among governments, private pharmaceutical companies and the academic community.
Dr. Meissner is professor of pediatrics at Floating Hospital for Children, Tufts Medical Center. He also is an ex officio member of the AAP Committee on Infectious Diseases and associate editor of the AAP Visual Red Book.
