Is Dengue Vaccine Protection Possible?

In tropical and subtropical countries, 4 dengue viruses (DENVs) produce mild disease and a potentially fatal vascular permeability syndrome. Unique antigenic and biological properties of DENVs contribute to vaccine development delays. Three tissue culture-based tetravalent candidate dengue vaccines have advanced to phase 3 clinical testing. Sanofi-Pasteur's chimeric yellow fever tetravalent dengue vaccine, Dengvaxia, licensed in 19 dengue-endemic countries, Europe, and the United States, partially protects seropositives but sensitizes some seronegatives to severe hospitalized dengue. During 2 years of phase 3, Takeda's TAK-003, a chimeric DENV 2 tetravalent vaccine, protected against DENV 2 but was less protective against other DENVs. In seronegative adults, 1 dose of a tetravalent nonstructural deletion mutant vaccine in late phase developed by the US National Institutes of Health protected seronegative humans against challenge with DENVs 2 and 3. This experience suggests nearly whole DENV genomes are required to achieve balanced and sustained protective immunity.

COVID-19 Vaccines: Should We Fear ADE?

Might COVID-19 vaccines sensitize humans to antibody-dependent enhanced (ADE) breakthrough infections? This is unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages. Severe disease centers on older persons with preexisting conditions and not infants or individuals with previous coronavirus infections. Live virus challenge of animals given SARS or MERS vaccines resulted in vaccine hypersensitivity reactions (VAH), similar to those in humans given inactivated measles or respiratory syncytial virus vaccines. Safe and effective COVID-19 vaccines must avoid VAH.

Biologic Evidence Required for Zika Disease Enhancement by Dengue Antibodies.

The sudden appearance of overt human Zika virus infections that cross the placenta to damage fetal tissues, target sexual organs, and are followed in some instances by Guillain-Barré syndrome raises questions regarding whether these outcomes are caused by genetic mutations or if prior infection by other flaviviruses affects disease outcome. Because dengue and Zika viruses co-circulate in the urban Aedes aegypti mosquito-human cycle, a logical question, as suggested by in vitro data, is whether dengue virus infections result in antibody-dependent enhancement of Zika virus infections. This review emphasizes the critical role for epidemiologic studies (retrospective and prospective) in combination with the studies to identify specific sites of Zika virus infection in humans that are needed to establish antibody-dependent enhancement as a possibility or a reality.

A relevant in vitro human model for the study of Zika virus antibody-dependent enhancement.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has recently been responsible for a serious outbreak of disease in South and Central America. Infection with ZIKV has been associated with severe neurological symptoms and the development of microcephaly in unborn fetuses. Many of the regions involved in the current outbreak are known to be endemic for another flavivirus, dengue virus (DENV), which indicates that a large percentage of the population may have pre-existing DENV immunity. Thus, it is vital to investigate what impact pre-existing DENV immunity has on ZIKV infection. Here, we use primary human myeloid cells as a model for ZIKV enhancement in the presence of DENV antibodies. We show that sera containing DENV antibodies from individuals living in a DENV-endemic area are able to enhance ZIKV infection in a human macrophage-derived cell line and primary human macrophages. We also demonstrate altered pro-inflammatory cytokine production in macrophages with enhanced ZIKV infection. Our study indicates an important role for pre-existing DENV immunity on ZIKV infection in primary human immune cells and establishes a relevant in vitro model to study ZIKV antibody-dependent enhancement.

Reappearance of chikungunya, formerly called dengue, in the Americas.

After an absence of ≈200 years, chikungunya returned to the American tropics in 2013. The virus is maintained in a complex African zoonotic cycle but escapes into an urban cycle at 40- to 50-year intervals, causing global pandemics. In 1823, classical chikungunya, a viral exanthem in humans, occurred on Zanzibar, and in 1827, it arrived in the Caribbean and spread to North and South America. In Zanzibar, the disease was known as kidenga pepo, Swahili for a sudden cramp-like seizure caused by an evil spirit; in Cuba, it was known as dengue, a Spanish homonym of denga. During the eighteenth century, dengue (present-day chikungunya) was distinguished from breakbone fever (present-day dengue), another febrile exanthem. In the twentieth century, experiments resulted in the recovery and naming of present-day dengue viruses. In 1952, chikungunya virus was recovered during an outbreak in Tanzania, but by then, the virus had lost its original name to present-day dengue viruses.

Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection.

Today, dengue viruses are the most prevalent arthropod-borne viruses in the world. Since the 1960s, numerous reports have identified a second heterologous dengue virus (DENV) infection as a principal risk factor for severe dengue disease (dengue hemorrhagic fever/dengue shock syndrome, DHF/DSS). Modifiers of dengue disease response include the specific sequence of two DENV infections, the interval between infections, and contributions from the human host, such as age, ethnicity, chronic illnesses and genetic background. Antibody-dependent enhancement (ADE) of dengue virus infection has been proposed as the early mechanism underlying DHF/DSS. Dengue cross-reactive antibodies raised following a first dengue infection combine with a second infecting virus to form infectious immune complexes that enter Fc-receptor-bearing cells. This results in an increased number of infected cells and increased viral output per cell. At the late illness stage, high levels of cytokines, possibly the result of T cell elimination of infected cells, result in vascular permeability, leading to shock and death. This review is focused on the etiological role of secondary infections (SI) and mechanisms of ADE.

Vaccine-Associated Enhanced Viral Disease: Implications for Viral Vaccine Development.

Vaccine-associated enhanced disease (VAED) is a serious barrier to attaining successful virus vaccines in human and veterinary medicine. VAED occurs as two different immunopathologies, antibody-dependent enhancement (ADE) and vaccine-associated hypersensitivity (VAH). ADE contributes to the pathology of disease caused by four dengue viruses (DENV) through control of the intensity of cellular infection. Products of virus-infected cells are toxic. A partially protective yellow fever chimeric tetravalent DENV vaccine sensitized seronegative children to ADE breakthrough infections. A live-attenuated tetravalent whole virus vaccine in phase III testing appears to avoid ADE by providing durable protection against the four DENV. VAH sensitization by viral vaccines occurred historically. Children given formalin-inactivated measles or respiratory syncytial virus (RSV) vaccines experienced severe disease during breakthrough infections. Tissue responses demonstrated that VAH not ADE caused these vaccine safety problems. Subsequently, measles was successfully and safely contained by a live-attenuated virus vaccine. The difficulty in formulating a safe and effective RSV vaccine is troublesome evidence that avoiding VAH is a major research challenge. VAH-like tissue responses were observed during breakthrough homologous virus infections in monkeys given severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) vaccines.

Japanese encephalitis: new options for active immunization.

Japanese encephalitis (JE) is a mosquito-borne flavivirus infection responsible for significant morbidity and mortality across Asia. Indigenous populations and those who undertake short- and long-term travel to endemic regions are at risk of infection and development of neuroinvasive disease. Effective mouse brain-derived vaccines have been available in select countries, including the United States, for decades. Limited access in Asia and safety concerns with regard to mouse brain products prompted the Chinese to develop a live, attenuated virus vaccine (SA14-14-2; Chengdu Institute of Biological Products), which has proven to be safe and efficacious following administration of >300 million doses. Recently, the portfolio of JE vaccines increased again with licensure in the United States, Europe, and Australia of a purified, inactivated virus JE vaccine (IC51; Intercell AG) and filing for licensure in Thailand and Australia of a Yellow fever-JE chimeric vaccine (ChimeriVax-JE; Sanofi Pasteur). JE is a vaccine-preventable disease with numerous options now available for active immunization. Aggressive and responsible vaccination programs should greatly diminish the burden of disease.

New vaccines for Japanese encephalitis.

Epidemics of encephalitis occurring throughout much of Asia are caused by Japanese encephalitis virus (JEV), a flavivirus maintained in a zoonotic cycle and transmitted by the mosquito, Culex tritaeniorhynchus. Resident populations, including short-or long-term visitors to enzootic regions, are at risk for Japanese encephalitis (JE) infection and disease. For the past several decades, effective killed viral vaccines prepared in tissue culture or mouse brain have been used to immunize travelers and residents of affected countries. Cost, efficacy, and safety concerns led to the development of a single-dose live attenuated virus vaccine (SA14-14-2) and more recently, to the licensure in the United States, Europe, and Australia of a purified inactivated, tissue culture-based JE vaccine (IC51; Intercell AG, Vienna, Austria) and the soon-to-be-licensed live-attenuated yellow fever-JE chimeric vaccine (ChimeriVax-JE; Sanofi Pasteur, Lyon, France). Safe and effective JE vaccines are now available to the entire at-risk population and should greatly diminish the burden of disease.

Ethics of a partially effective dengue vaccine: Lessons from the Philippines.

Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine developed by SanofiPasteur is widely licensed in dengue-endemic countries. In a large cohort study Dengvaxia was found to partially protect children who had prior dengue virus (DENV) infections but sensitized seronegative children to breakthrough DENV disease of enhanced severity. In 2019, the European Medicines Agency and the US FDA issued licenses that reconciled safety issues by restricting vaccine to individuals with prior dengue infections. Using revised Dengvaxia efficacy and safety data we sought to estimate hospitalized and severe dengue cases among the more than 800,000 9 year-old children vaccinated in the Philippines. Despite an overall vaccine efficacy of 69% during 4 years post-vaccination we project there will be more than one thousand vaccinated seronegative and seropositive children hospitalized for severe dengue. Assisting these children through a program of enhanced surveillance leading to improved care deserves widespread support. Clinical responses observed during breakthrough dengue infections in vaccinated individuals counsel prudence in design of vaccine policies. Recommendations concerning continued use of this dengue vaccine are: (1) obtain a better definition of vaccine efficacy and safety through enhanced phase 4 surveillance, (2) obtain a valid, accessible, sensitive, specific and affordable serological test that identifies past wild-type dengue virus infection and (3) clarify safety and efficacy of Dengvaxia in flavivirus immunes. In the absence of an acceptable serological screening test these unresolved ethical issues suggest Dengvaxia be given only to those signing informed consent.

Dengue 1 virus and dengue hemorrhagic fever, French Polynesia, 2001.

An epidemic of dengue 1 virus (DENV-1) occurred in French Polynesia in 2001, 4 years after a DENV-2 epidemic that ended in 1997. Surveillance data from hospitalized case-patients showed that case-patients with dengue hemorrhagic fever (DHF) exhibited a bimodal age distribution with 1 peak among infants 6-10 months of age and a second peak at 4-11 years of age. The relative risk of DHF developing in children born before rather than after the DENV-2 epidemic was 186 (95% confidence interval 26-1,324). Among children born toward the end of the DENV-2 epidemic, a strong temporal association was found between the month of birth and the risk of being hospitalized for DHF. This study documents epidemic pathogenicity associated with the sequence of DENV-2 infection followed by DENV-1 infection.

Evaluation of commercially available anti-dengue virus immunoglobulin M tests.

Anti-dengue virus immunoglobulin M kits were evaluated. Test sensitivities were 21%-99% and specificities were 77%-98% compared with reference ELISAs. False-positive results were found for patients with malaria or past dengue infections. Three ELISAs showing strong agreement with reference ELISAs will be included in the World Health Organization Bulk Procurement Scheme.