Vaccine regulatory approval during outbreaks: The prognosis for Zika
As the Zika virus has emerged on the global stage as the latest major infectious disease epidemic, governments and public health agencies are rapidly gearing up in response. At the beginning of February, the World Health Organization (WHO) declared a global public health emergency over the cases of neurological disorders thought to be linked with Zika infection, Guillain-Barré syndrome and the birth defect microcephaly. Even if a specific treatment for Zika were available, it is tricky to tell who has been infected: 80% of infected people do not feel ill, and the remaining 20% usually show mild symptoms. As a result, prevention efforts are the focus in the Central and South American countries where Zika is actively spreading.
While current prevention approaches target the mosquitos that transmit Zika, administering a protective vaccine would be ideal. As the push to develop a vaccine begins, the big question is how long the process might take. From identifying a potential vaccine candidate through testing and approval by the U.S. Food and Drug Administration (FDA), the typical development timeline is on the order of fifteen years. The scientific challenges of working on such an understudied disease as Zika are not insignificant, but preclinical development will be informed by existing vaccines for viruses in the same flavivirus genus; the yellow fever vaccine has been in use for several decades, the first dengue vaccine was approved in Mexico at the end of last year, and a West Nile vaccine candidate is currently in phase 1 clinical testing. Although Zika vaccine development is starting in the preclinical stages, looking ahead to clinical trials brings up both challenges and potential for timely regulatory approval.
A major challenge for Zika clinical trials is that vaccine candidates should be tested in pregnant women, but a specific FDA approval pathway for such studies currently does not exist. To date, no vaccines on the U.S. market are licensed for use in pregnant women. Typically, disease treatment for infants is administered after birth. In cases such as influenza, pregnant women receive the vaccine despite the lack of approved safety and efficacy data for mothers or their infants. Traditionally, these populations have been excluded from clinical trials due to potential toxicity in the developing fetus, as well as the preexisting range of risks to women during pregnancy.
Zika vaccine candidates will require a different evaluation approach because there is an association of microcephaly in infants born to women who are infected while pregnant. Since Zika vaccine candidates should be protective in pregnant women, FDA guidelines must be developed for clinical trials in this population. For example, a phase 3 trial in the general population could be conducted before testing in pregnant women, in order to ensure a high degree of vaccine candidate safety. If measuring the outcome of microcephaly incidence would not be feasible within a reasonable timeframe, an alternate measure of vaccine candidate efficacy should be validated, such as a protective immune response in the women. Such regulatory guidelines should be developed while Zika vaccine candidates undergo preclinical studies, so that progression to clinical trials can be as efficient as possible.
Though Zika vaccine trials will face challenges due to the virus’s specific pathology, the recent Ebola epidemic in West Africa highlights the potential for the rapid implementation of a vaccine candidate in case of a public health emergency. After the WHO recognized the Ebola epidemic in early 2014, vaccine candidates with promising preclinical results in macaque monkeys were quickly moved to human trials. In particular, the rVSV-ZEBOV vaccine candidate by Merck was first given to healthy volunteers over the short period of November 2014 to January 2015. This phase 1 trial showed that rVSV-ZEBOV was generally safe and generated an immune response against part of the Ebola virus.
Following the successful phase 1 trial, Merck coordinated with the FDA to implement phase 2 and 3 trials that could both demonstrate vaccine efficacy and provide care to those at risk for infection. The phase 3 trial that started in Guinea in April 2015 had a unique design. In a standard trial, the vaccine candidate is compared to a placebo or unrelated vaccine. Because it would be unethical to give a placebo to individuals at high risk for such a severe disease as Ebola, rVSV-ZEBOV was given to all individuals in the trial using a ring vaccination scheme. For patients known to have Ebola, rVSV-ZEBOV was administered to clusters of their contacts, as well as contacts of contacts. By comparing immediate vaccination with delayed vaccination of the contact rings surrounding patients, the trial’s preliminary results in July 2015 showed that rVSV-ZEBOV was highly effective in protecting against infection. Currently, with much lower Ebola transmission in the region, this trial and another phase 3 trial in Sierra Leone are still ongoing. These ring vaccination trials demonstrate a potential regulatory mechanism to expedite Zika vaccine clinical testing during an epidemic.
Overall, the prognosis for Zika vaccine development is promising. The current epidemic marks the first recognition of the virus as an important human pathogen, so the rush to develop prevention strategies has just begun. However, in the realm of preclinical vaccine testing, methods used for other flavivirus vaccines could be applicable. During preclinical development, the FDA should solidify regulatory guidelines for clinical trials in pregnant women. If a Zika vaccine candidate becomes ready for clinical testing during the current outbreak or a future one, then alternate trial designs such as ring vaccination can provide protection to at-risk individuals while demonstrating efficacy. Ultimately, timely responses and flexibility throughout the vaccine regulatory process are crucial for successful public health efforts.
Jessica Lau is a staff writer covering regulatory affairs for HPHR Now. Jessica is a PhD student at the Harvard T.H. Chan School of Public Health in the Department of Immunology and Infectious Diseases where she studies the evolution of bacteria and viruses.
