Implications of vaccine non-specific effects on licensure of new vaccines.

Immune memory was for a long time thought to be an exclusive feature of the adaptive immune system. Emerging evidence has shown that the innate immune system may exhibit memory which has been termed as trained immunity or innate immune memory. Trained immunity following vaccination may produce non-specific effects leading to reduction in morbidity and mortality from heterologous pathogens. This review looked at trained immunity as a mechanism for vaccine induced non-specific effects, mechanisms underlying trained immunity and known vaccine non-specific effects. A discussion is also made on the implications these vaccine non-specific effects may have on overall risk-benefit ratio evaluation by National Medicines Regulatory Authorities (NMRAs) during licensure of new vaccines. Epigenetic remodeling and "rewiring" of cellular metabolism in the innate immune cells especially monocytes, macrophages, and Natural Killer (NK) cells have been suggested to be the mechanisms underlying trained immunity. Trained immunity in other innate cells has largely remained elusive up to date. Non-specific effects have been extensively documented with Bacille Calmette-Guerin (BCG), measles vaccine and oral polio vaccine but it remains unclear if other vaccines may exhibit similar effects. All known vaccine non-specific effects have come from observations in epidemiological studies conducted post-vaccine licensure and roll out in target populations. It remains to be seen if early identification of non-specific effects especially those with protective benefits during the clinical development of new vaccines may contribute to the overall risk-benefit ratio evaluation during licensure by NMRAs.

Vaccine Licensure in the Absence of Human Efficacy Data.

Clinical vaccine development and regulatory approval generally occurs in a linear, sequential manner: Phase 1: safety, immunogenicity; Phase 2: immunogenicity, safety, dose ranging, and preliminary efficacy; Phase 3: definitive efficacy, safety, lot consistency; and following regulatory approval, Phase 4: post-marketing safety and effectiveness. For candidate filovirus vaccines, where correlates of protection have not been identified, and phase 2 and 3 efficacy of disease prevention trials untenable, large and/or protracted, each trial may span decades, with full licensure expected only after several decades of development. Given the urgent unmet need for new Marburg virus and Ebola Sudan virus vaccines, the Sabin Vaccine Institute hosted a key stakeholder virtual meeting in May 2021 to explore the possibility of licensure by use of an "animal rule-like" licensure process, based on a risk/benefit assessment specific to regional needs and informed by epidemiology. This may be appropriate for diseases where there are no or limited treatment options, and those prone to sporadic outbreaks with high rates of transmission, morbidity, and mortality. The discussion focused on two contexts: licensure within the Ugandan regulatory environment, a high burden country where Ebola vaccine trials are ongoing, and licensure by the United States FDA-a well-resourced regulatory agency.

Effect of Efavirenz on Endogenous Progesterone Concentrations and Contraceptive Outcomes among Ugandan HIV Infected Women Coadministering Ethinylestradiol/Levonorgestrel.

This study assessed the effect of efavirenz mid-dose plasma concentrations on mid-luteal endogenous progesterone concentrations and contraceptive outcomes among 49 HIV infected women coadministering ethinylestradiol/levonorgestrel, including 34 HIV positive women on Highly Active Antiretroviral Therapy (HAART) and 15 HAART naïve HIV infected women, purposively selected from Mulago Hospital, Uganda. A blood sample was collected once between days 20 and 22 of each woman's menstrual cycle for measuring endogenous progesterone and efavirenz concentrations by electrochemiluminescence technology and High Performance Liquid Chromatography (HPLC), respectively. Descriptive statistical analysis and correlation and logistic regression analysis were done using SPSS v.21 and R3.1. Efavirenz showed a weak positive linear relationship with endogenous progesterone at efavirenz concentrations below 12 µg/ml. Based on serum endogenous progesterone, the observed hormonal contraceptives failure rate (24.5%) was higher than expected (maximum 8%). A higher proportion of HIV positive women on efavirenz based HAART (26.5%) was at risk of contraceptive failure than their HIV infected HAART naïve counterparts (20%) though it was not statistically significant (p = 0.63). Efavirenz mid-dose plasma concentrations seem to have no significant effect on mid-luteal endogenous progesterone concentrations and contraceptive outcomes among HIV infected Ugandan women coadministering ethinylestradiol/levonorgestrel oral pills.