Vaccination of Human Volunteers With Monovalent and Tetravalent Live-Attenuated Dengue Vaccine Candidates

Abstract

Abstract. Four serotypes of monovalent live attenuated dengue virus vaccine candidates were tested for reactogenicity and immunogenicity in 49 flavivirus non-immune adult human volunteers. The four monovalent candidates were then combined into a tetravalent formulation and given to another 10 volunteers. Neutralizing antibody seroconversion rates after a single-dose monovalent vaccination ranged from 53% to 100%. Solicited reactogenicity was scored by each volunteer. A composite index, the Reactogenicity Index, was derived by these self-reported scores. Reactogenicity differed among the four serotype candidates with serotype-1 associated with the most vaccine related side effects. A second dose of monovalent vaccines at either 30 days or 90 days was much less reactogenic but did not significantly increase seroconversion rates. Seroconversion rates in the 10 volunteers who received a single dose of tetravalent vaccine ranged from 30% to 70% among the four serotypes. Similar to the monovalent vaccines, a second dose of the tetravalent vaccine at one month was less reactogenic and did not increase seroconversion. A third dose of the tetravalent vaccine at four months resulted in three of four volunteers with trivalent or tetravalent high-titer neutralizing antibody responses.

Instabilities in multiserotype disease models with antibody-dependent enhancement

“…Therefore, we find y 4 oz 2 þ z 4 because 0on 2 À 2n þ 2 for all n 2 R, and conclude that single-serotype vaccinations could potentially increase the number of DHF cases for ADE values associated with an endemic steady-state in the non-vaccination model (before the Hopf bifurcation). We note that single serotype vaccines have been tested in populations with no exposure to dengue and found to have 53-100% seroconversion rates (Sun et al, 2003). No singleserotype vaccines are being evaluated among persons at risk of exposure to dengue nor being designed for routine use because it is assumed that this would have a negative impact on health in any setting.…”

Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

“…An effective DENV vaccine should confer protection for each serotype since all four serotypes commonly circulate in endemic regions, and secondary infection with a heterologous serotype is associated with increased disease severity [9]. Unfortunately, previous attempts to develop a tetravalent, live attenuated vaccine against the DENV have found that one or more vaccine components exhibited either under-or over-attenuation resulting in unacceptable reactogenicity or poor immunogenicity, respectively [10,11]. Modification of the concentration of one of the serotypes in a tetravalent vaccine has not been able to reliably correct problems of reactogenicity or over-attenuation [12][13][14].…”

Assessing the interest to participate in a dengue vaccine efficacy trial among residents of Puerto Rico

“…7 Given the lack of effective tools for the primary prevention of dengue, there has been a major effort to develop safe and effective dengue vaccines as a tool to prevent this disease. [10][11][12][13][14] Several dengue vaccines are now in late stage development and will begin to move into large scale clinical trials. [15][16][17] Because dengue is endemic in Puerto Rico, it has been considered as a potential site for a dengue vaccine efficacy trial.…”