A. X. Mo
National Institutes of Health, Rockville, MD
- Explain the scientific rationale for different malaria vaccine designs
- Describe various malaria vaccines in development
- Discuss what it would take to drive malaria vaccine development to the final finish line
Malaria is a devastating disease and is the number one killer of children in underdeveloped countries. According to the latest World Malaria Report, despite enormous investments in global malaria control and elimination programs, progress towards malaria control and elimination has stalled in recent years. There were still 219 million cases and 445,000 deaths worldwide due to malaria in 2018. In addition, increased drug resistance and insecticide resistance and changes in vector behavior that compromise other interventions have generated concerns about the long-term viability of current interventions. Vaccines remain a potentially valuable tool to combat this devastating disease. However, development and evaluation of malaria vaccines have proven to be technically challenging and financially burdensome. The most advanced vaccine product, RTS,S/AS01B, which is currently being rolled out in a few selected African countries, only approaches a moderate level of efficacy with short duration against clinical malaria at 33-50% in older infants. In this presentation, the global malaria vaccine landscape will be reviewed, and development strategies and efforts for an improved, second-generation malaria vaccine will be discussed.
1. Beeson JG, Kurtovic L, Dobaño C, Opi DH, Chan JA, Feng GF, Reiling L, Boyle MJ, Challenges and strategies for developing efficacious and long-lasting malaria vaccines. Sci Transl Med. 2019 Jan 9;11(474).
2. de Vrieze J. A shot of hope, Science. 2019 Nov 29;366(6469):1062-1065.
3. RTS, S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomized, controlled trial. Lancet Lond Engl. 2015;386(9988):31–45.
Typhoid Vaccines for the Global Market
K. M. Neuzil
University of Maryland School of Medicine, Baltimore, MD
Describe the global typhoid conjugate vaccine recommendations, the latest data on safety and efficacy, and the status of country introduction.
In 2018, the World Health Organization (WHO) released updated recommendations on the use of typhoid vaccines to prevent typhoid fever. Noting the continued high burden of typhoid fever and the alarming increase in antimicrobial resistance (AMR) in low- and middle-income countries, WHO recommended a single dose of typhoid conjugate vaccine (TCV) in typhoid-endemic countries for children 6 months of age and older, plus catch-up vaccination for children up to 15 years of age. The WHO further stated that decisions on the age of TCV administration, target population, and delivery strategy for routine and catch-up vaccination should be based on the local epidemiology of typhoid fever, including AMR patterns, and programmatic considerations of the routine childhood immunization program. WHO recommended prioritization to countries with the highest burden of disease or a high burden of antimicrobial-resistant S. Typhi. Importantly, Gavi, the Vaccine Alliance (Gavi) opened a funding window for TCV support, and committed US $85 million to support TCVs in Gavi-eligible countries.
In 2019, TCV was successfully and safely used for outbreak response in Zimbabwe and Pakistan. In February, Zimbabwe led the way with the first-ever outbreak response vaccination campaign against typhoid in sub-Saharan Africa. The vaccine was used in Pakistan in April 2019 as part of the response to the current extensively drug resistant (XDR) typhoid outbreak. On November 18th, Pakistan became the first country to introduce TCVs into their routine immunization program. By the end of 2019, 9.8 million children in Pakistan had been vaccinated with TCV. Additional country introductions are planned for 2020.
Ongoing trials in Bangladesh, Burkina Faso, Malawi, and Nepal, and a vaccine introduction effort in Navi Mumbai, India, continue to affirm the safety and immunogenicity of the vaccine. Recently published interim results from the first year of the clinical study in Nepal show a single dose of the vaccine prevented more than 80 percent of typhoid cases in children as young as 9 months old in an endemic setting. Forthcoming data will continue to inform additional country uptake and programmatic use of TCV.
1. Shakya M, Colin-Jones R1, Theiss-Nyland K, Voysey M, Pant D, Smith N, Liu X, Tonks S, Mazur O, Farooq YG, Clarke J, Hill J, Adhikari A, Dongol S, Karkey A, Bajracharya B, Kelly S, Gurung M, Baker S, Neuzil KM, Shrestha S, Basnyat B, Pollard AJ; TyVAC Nepal Study Team. Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal. New England Journal of Medicine. 2019 December 5; 381(23):2209-2218. doi: 10.1056/NEJMoa1905047.
2. Pollard AJ, Marfin AA, Neuzil KM. The time is now to control typhoid. Clin Infect Dis. 2019 March 7;68(Supplement_2):S47-S49. doi:10.1093/cid/ciy1115.
3. Bilcke J, Antillon M, Pieters Z, Kuylen E, Abboud L, Neuzil KM, Pollard AJ, Paltiel AD, Pitzer VE. Cost-effectiveness of typhoid conjugate vaccine delivery strategies in Gavi-eligible countries: a modelling study. Lancet Global Health. 2019 May 23; DOI: https://doi.org/10.1016/S1473-3099(18)30804-1.
The Rotavirus Vaccination Story: A Parable of Trials, Tribulations, and Ultimate Successes in Vaccine Development
H. B. Greenberg
Stanford University, Stanford, CA
- Describe the discovery process that led to identifying rotaviruses as the single most important cause of severe infantile diarrhea around the world
- Explain the process used to determine that a vaccine would be the most appropriate and likely most successful intervention for decreasing rotavirus morbidity and mortality
- Describe the challenges involved in developing successful vaccines
- Predict where the field of rotavirus vaccinology is likely headed
Human rotaviruses (RV) were discovered in 1973. Within just a few years their epidemiologic importance as the single most important cause of severe infantile diarrhea everywhere in the world was well established. Because rotavirus infection was found to occur primarily in the small bowel, in mature villus tip cells, emphasis was placed on developing a mucosal immunization strategy. Since human rotaviruses circulated multiple distinct “serotypes,” emphasis was initially focused on developing multivalent vaccine candidates. While these initial approaches were seemingly logical, from the start available data implied they might not be entirely correct.
The first RV vaccine candidate to be licensed was developed at the National Institutes of Health (NIH) and was a quadrivalent reassortant vaccine representing the 4 most common human RV serotypes on a single simian (rhesus) RV (RRV) genetic backbone. This vaccine was shown to be “safe and effective” and was licensed in the US in the late 1990s. Post-licensure surveillance disclosed an association between intussusception and the RRV-based vaccine leading to its rapid and complete removal from the marketplace. The level of risk associated with the RRV-based vaccine, risk/benefit analysis associated with its removal, and the risk of intussusception with subsequent RV vaccines continue to be topics of interest to many.
Following a 7- to 8-year delay, 2 new live attenuated RV vaccines were licensed—one also being a multivalent based on a bovine RV genetic backbone, the other second generation RV vaccine being a single serotype human RV attenuated by cell culture passage. Both were found equally safe and effective in studies carried out in developed countries, but substantially less effective in the poorest countries of the world. The fact that a single serotype vaccine was broadly protective surprised some investigators although prior epidemiologic data clearly supported the likelihood of heterotypic immunity to RV. Subsequently, very large-scale data-based studies found that the second-generation RVs were also associated with a small increased risk of intussusception, but that their risk was outweighed by their benefit. An understanding as to why the second generation RV vaccines are substantially less effective in poor countries is not yet available.
Efforts are currently directed at improving efficacy and lowering cost of third-generation RV vaccines for less developed countries. Cost has been lowered by developing vaccine manufacturing capacity in these countries. New approaches aimed at improving vaccine efficacy will be briefly discussed.
1. Franco M, Greenberg HB. Rotaviruses, Noroviruses and Other Gastrointestinal Viruses. In: Goldman- Cecil Medicine, 26th Edition, Chapter 356. P2210-2213, Elsevier Press, 2020.