Dengue Fever Vaccine Side Effects And Development Obstacles

Dengue fever（DF）is an acute infectious disease caused by mosquito-borne dengue virus, which is prevalent in more than 100 countries and regions in Southeast Asia, the Western Pacific, Central and South America, the Caribbean and Africa. About 400 million people are infected each year, most of whom show no symptoms or only a low-grade fever, but some develop the life-threatening dengue shock syndrome. Vaccination is the best way to prevent disease. The ideal DF vaccine should be safe and effective. From the 1920s to the present, the research on DF vaccine has gone through more than 80 years. Although there are currently available vaccines on the market, the effect is not satisfactory. There are many reasons that hinder the progress of vaccine research. This article reviews the dengue fever vaccine side effects and development obstacles.

1. Epidemiological factors are complex

Dengue virus（DENV）is mainly transmitted by Aedes aegypti and Aedes albopictus and is prevalent in tropical and subtropical regions. In recent years, affected by factors such as climate and environmental changes, human travel, rapid urbanization, etc., DENV has a tendency to spread to a larger geographical area every year, and the epidemic characteristics have gradually developed from one or two serotypes, sporadic outbreaks. For 4 serotypes, large outbreaks, the infected population also expanded from children to adolescents and adults. In some areas, DENV often manifests as co-circulation and mixed prevalence of multiple serotypes, and it is difficult to predict which serotype is dominant at different time points. Therefore, the protective efficacy of each serotype vaccine needs to be measured in a large number of volunteers at multiple trial sites over a long period of time, making clinical trials of vaccines more difficult. Another problem is that genetic variation may occur within serotypes, and each serotype of DENV is divided into multiple genotypes, which makes vaccine research more difficult. In conclusion, the perennial spread of multiple serotypes in an area makes it possible for immune-mediated cross-protection and infection-enhancing effects to contaminate each other, leading to certain dengue fever vaccine side effects.

2. The pathogenesis of infection and immune protection mechanism are not clear

The primary infection of DENV induces B lymphocytes to produce type I specific neutralizing antibodies as well as cross-reactive, weak or non-neutralizing antibodies. This adaptive immune response provides lifelong immunity against DENV of the same serotype, but cross-protection against DENV of the different serotype only lasts for a few months, after which the immune memory may enhance pathogenicity rather than protect against secondary infection. In addition, infants with maternal weakened antibodies are also prone to severe DF at the time of primary infection, because the preexistence of heteromorphic antibodies in their bodies makes the primary infection similar to the secondary infection. Another pathogenic mechanism is the cytokine storm theory. According to the theory, when the body fights against atypical DENV infection, cross-reactive memory T cells release a large number of pro-inflammatory cytokines and cause vascular leakage, which promotes the infection to develop into atypical secondary infection. In addition, the correlation between the response amplitude of CD8+T cells and the severity of the disease has been confirmed during acute infection, which also indicates that the heteromorphic secondary infection may be dominated by the cross-reactive and low-affinity memory T cells induced by the primary infection. However, some studies have shown that there is no correlation between the intensity of T cell response and the severity of disease in secondary DENV infection, and it even plays a protective role. Complement activity is also thought to be associated with severe DF. In DSS patients, the level of terminal complement C5B-9 was associated with disease severity. Allergic toxins such as C5B-9 have also been shown to promote plasma leakage and play an important role in the pathological process of severe DF.

3. Lack of effective animal models

Because DENV is primarily pathogenic in humans, there is no animal model that can accurately mimic the symptoms and immune response of DENV infection in humans. The currently used animal models have great limitations, such as careful selection of suitable animal models for some special studies and careful interpretation of test results. In recent years, the animal models used for the development of DF vaccines only include mice, non-human primates, rabbits, and miniature pigs, which cannot effectively help the development of dengue vaccines and are not conducive to eliminating the dengue fever vaccine side effects.

Due to the existence of the above obstacles, resulting in the use of dengue fever vaccine side effects. According to clinical statistical analysis data, for people who have not been infected with dengue fever, if they are infected with dengue fever virus after vaccination, more serious diseases may occur. Common side effects include headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever.

To sum up, although there are some difficulties in the research and development of dengue vaccine, many research institutions are making active efforts, and good results have been achieved in the characteristics of dengue virus, production technology of dengue vaccine, evaluation of vaccine immunization effect and overcoming the dengue fever vaccine side effects. It is foreseeable that in the near future, a safe vaccine with good immune effect can be developed to meet the needs of dengue control.