Dengue, a major public health problem throughout subtropical and tropical regions, is an acute infectious disease characterized by biphasic fever, headache, pain in various parts of the body, prostration, rash, lymphadenopathy, and leukopenia. In more severe or complicated dengue, patients present with a severe febrile illness characterized by abnormalities of hemostasis and increased vascular permeability, which in some instances results in a hypovolemic shock. Four distinct serotypes of the dengue virus (dengue-1, dengue-2, dengue-3, and dengue-4) exist, with numerous virus strains found worldwide. Molecular cloning methods have led to a greater understanding of the structure of the RNA genome and definition of virus-specific structural and nonstructural proteins. Progress towards producing safe, effective dengue virus vaccines, a goal for over 45 years, has been made. Images

The dengue viruses.

Encephalitis caused by Japanese encephalitis virus occurs in annual epidemics throughout Asia, making it the principal cause of epidemic viral encephalitis in the world. No currently available vaccine has demonstrated efficacy in preventing this disease in a controlled trial. We performed a placebo-controlled, blinded, randomized trial in a northern Thai province, with two doses of monovalent (Nakayama strain) or bivalent (Nakayama plus Beijing strains) inactivated, purified Japanese encephalitis vaccine made from whole virus derived from mouse brain. We examined the effect of these vaccines on the incidence and severity of Japanese encephalitis and dengue hemorrhagic fever, a disease caused by a closely related flavivirus. Between November 1984 and March 1985, 65,224 children received two doses of monovalent Japanese encephalitis vaccine (n = 21,628), bivalent Japanese encephalitis vaccine (n = 22,080), or tetanus toxoid placebo (n = 21,516), with only minor side effects. The cumulative attack rate for encephalitis due to Japanese encephalitis virus was 51 per 100,000 in the placebo group and 5 per 100,000 in each vaccine group. The efficacy in both vaccine groups combined was 91 percent (95 percent confidence interval, 70 to 97 percent). Attack rates for dengue hemorrhagic fever declined, but not significantly. The severity of cases of dengue was also reduced. We conclude that two doses of inactivated Japanese encephalitis vaccine, either monovalent or bivalent, protect against encephalitis due to Japanese encephalitis virus and may have a limited beneficial effect on the severity of dengue hemorrhagic fever.

https://www.nejm.org/doi/pdf/10.1056/NEJM198809083191004?listPDF=true

Protection against Japanese Encephalitis by Inactivated Vaccines

Summary Non-neutralizing, serotype-specific anti-NS1 monoclonal antibodies partially protected passively immunized mice from lethal dengue 2 virus intracerebral challenge. There was no apparent correlation between complement-fixing activity and protective capacity among individual anti-NS1 monoclonal antibodies. Immunization with specific combinations of non-protective or partially protective antibodies resulted in prolonged survival or reduced mortality. Solid protection, equal to that achieved after immunization with neutralizing polyclonal antibody, was achieved only with an antibody pair which individually fixed complement to high titre with homologous virus. Some groups of mice had increased morbidity after immunization with combinations of protective monoclonal antibodies that bind to overlapping epitopes. These results may affect the design of recombinant dengue vaccines which may require the inclusion of serotype-specific antigenic domains.

Synergistic Interactions of Anti-NS1 Monoclonal Antibodies Protect Passively Immunized Mice from Lethal Challenge with Dengue 2 Virus

2 – Antigenic Characteristics and Classification of Togaviridae

A retrospective serological survey for dengue immunity was conducted in Nigeria to determine the prevalence of infection in man and non-human primates. Preliminary haemagglutination-inhibition (HI) tests revealed that 63% of persons tested had HI antibodies against one or more of the following flaviviruses: dengue type 1, yellow fever, West Nile and Wesselsbron. Parallel HI and neutralization (N) tests on 179 human sera showed that six of 20 sera (30%) negative for flavivirus HI antibody contained dengue N antibody. This finding emphasized the advantage of the N test over HI in screening for dengue virus immunity. Neutralization tests performed on 1,816 human sera from different geographical locations in Nigeria showed that 45% of Nigerians were immune to dengue type 2 virus. The percentage of immunity in adults aged 20 years and older (51%) was significantly higher than in children (37%) (P less than 0-01). In all four ecological zones sampled, the highest percentage of dengue N antibody was observed in the derived Savannah zone (63%) followed by the rain forest zone (42%). The Southern Guinea savannah and plateau zones had lower percentages of dengue-immune persons. There was a higher prevalence of antibodies in urban (48%) than in rural communities (37%). Tests on dengue-immune sera showed that 35% of such sera contained N antibodies to dengue only or to dengue and one other virus. Therefore, dengue immunity cannot be explained by heterologous cross reactions within the flavivirus group. In addition, evidence of dengue infection was found in monkeys and galagos. 48% of monkeys and 25% of galagos contained dengue N antibody. The presence of specific dengue N antibodies in a few sera suggests that the occurrence of a forest cycle of dengue is possible in Nigeria.

Dengue virus infections in Nigeria: a survey for antibodies in monkeys and humans.

Spider monkeys immunized sequentially with living 17D yellow fever virus, living attenuated Langat E5 virus, and living attenuated dengue 2 virus (New Guinea C isolate) responded with high hemagglutinating-inhibition antibody titers against 21 Group B arbovirus antigens that were tested. Such monkeys also responded with neutralizing antibodies against 20 Group B arboviruses that were tested. These vaccinated monkeys were protected against subcutaneous challenges with dengue serotypes 1, 2, 3 or 4, Russian spring-summer encephalitis virus, Kyasanur Forest Disease virus, Omsk hemorrhagic fever virus, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile virus, and Kadam virus. The protection against these viruses was based on a much lower viremia, or absence of histologic lesions in the central nervous system, or absence of an antibody booster response. The 3-virus sequential immunized spider monkeys were also protected against Modoc virus as determined by viremia studies, in spite of the fact that no detectable serum neutralizing antibodies were found in these animals at the time of challenge. The development of the sequential immunization procedure is discussed.

Sequential immunization procedure against Group B arboviruses using living attenuated 17D yellow fever virus, living attenuated Langat E5 virus, and living attenuated dengue 2 virus (New Guinea C isolate).

Walter O'Leary

Papers

Sequential immunization procedure against Group B arboviruses using living attenuated 17D yellow fever virus, living attenuated Langat E5 virus, and living attenuated dengue 2 virus (New Guinea C isolate).