Emerging and Reemerging Aedes-Transmitted Arbovirus Infections in the Region of the Americas

Implications for Health Policy

Marcos A. Espinal, MD, DrPH; Jon K. Andrus, MD; Barbara Jauregui, MD, MSc; Stephen Hull Waterman, MD, MPH; David Michael Morens, MD; Jose Ignacio Santos, MD, MSc; Olaf Horstick, PhD (DrMed), FFPH, MPH, MSc, MBBS; Lorraine Ayana Francis, DrPH, MHA; Daniel Olson, MD

Disclosures

Am J Public Health. 2019;109(3):387-392. 

In This Article

Vaccines Against Aedes-transmitted Arbovirus

Because of the challenges related to vector control described previously, vaccines may well emerge as the most efficient tools for controlling and preventing Aedes-transmitted arbovirus infections. Currently, there are only 2 licensed vaccines against emerging and reemerging arboviruses in the Americas: the live attenuated yellow fever 17D vaccine and a recently licensed live attenuated chimeric yellow fever–derived tetravalent dengue vaccine (CYD-TVD). Although no vaccines are yet licensed against ZIKV or CHIKV, several candidate vaccines are in different phases of clinical trials.

Yellow Fever Vaccines

The live, attenuated yellow fever 17D vaccine developed in 1936 is one of the oldest live attenuated vaccines in current use.[44] The vaccine is widely used for the prevention of yellow fever in travelers, for routine immunization of infants in endemic areas, and for emergency response during outbreaks. Twenty to 60 million doses are distributed annually.[26]

Yellow fever 17D vaccine elicits a rapid, exceptionally strong, and essentially lifelong adaptive immune response. Vaccinologists have harnessed 17D as a vector for foreign genes,[26] a promising area for continued research.

Two types of severe adverse events are temporally associated with the yellow fever 17D vaccine: neurotropic and viscerotropic disease. Both are fortunately rare. Yellow fever vaccine–associated neurotropic disease is manifest in more than half of the cases by meningitis or encephalitis, and the remainder have clinical or radiological evidence for Guillain-Barré or acute disseminated encephalomyelitis. Neurotropic adverse events occur between 0.2 (Europe) and 0.8 (United States) per 100 000 population vaccinated. Most cases are in infants aged younger than 7 months. In 1960, recommendations were made contraindicating vaccine use in infants up to 6 months of age.[26] Recent reports have documented yellow fever 17D virus transmission, with resulting yellow fever vaccine–associated neurotropic disease, in 3 breastfed newborn babies from mothers who had been recently vaccinated.[26]

In 2001, 7 cases (6 fatal) of viscerotropic disease were reported with acute multiorgan failure. Such cases are caused by the 17D virus and resemble cases caused by wild-type YFV. Over the next 10 years, a total of 65 cases have been recorded, with a high case fatality rate of 63%. Fortunately, yellow fever vaccine–associated neurotropic disease remains rare. The risk is higher with advancing age, reaching 1.0 to 2.3 per 100 000 in persons aged older than 60 years, and is associated with impaired immunity. Despite the higher reporting rate in the elderly, severe disease and deaths have also occurred in young persons and in women of childbearing age.[26]

Countries in the Americas follow PAHO's Technical Advisory Group's recommendations to prevent and control yellow fever in the region, which include (1) universal introduction of the yellow fever vaccine in national immunization programs for children aged 1 year in countries with endemic transmission, (2) preventive vaccination campaigns for populations aged younger than 2 years living in enzootic areas during interepidemic periods, (3) vaccination campaigns in response to outbreaks or epizootics, and (4) vaccination of travelers to areas with a risk of YFV transmission.[45]

Unfortunately, the limited vaccine availability does not allow countries to fully implement these recommendations. The vaccination coverage in children at 1 year of age is approximately 70% in the region. Recent outbreaks of yellow fever in Angola and the Democratic Republic of Congo depleted the global vaccine stockpile, highlighting the challenges to maintaining supply. To address the shortage, on the basis of existing published data, experts have recommended fractional doses to administer reduced volumes of the vaccines.[46,47]

Dengue Vaccines

Vaccine development against DENV infections is among the most complex challenges in vaccinology, complicated by 2 major issues. First, DENV comprises 4 antigenically distinct serotypes with several genotypes within each serotype. Infection with 1 serotype generally confers lifelong immunity to the infecting serotype and only transient cross-protection to heterologous serotypes. Secondary infection expands the cross-reactive immunity, making symptomatic infections by a third DENV serotype unusual. However, inducing protection to all 4 DENV serotypes by 1 vaccine has been difficult. Second, severe manifestations of dengue occur at a higher rate in secondary infections. Antibody-dependent enhancement has been proposed as a mechanism to explain the more severe presentation of dengue in a secondary infection. During antibody-dependent enhancement, cross-reactive but nonneutralizing antibodies from primary infection by a heterologous DENV serotype enhance entry and replication of virus particles in immune cells, especially macrophages, resulting in high titers of virus in blood and consequently severe disease during the second DENV infection. Thus, a DENV vaccine carries the potential for increasing the risk of severe disease in DENV-naïve individuals unless the vaccine gives rise to lasting, protective immunity to all serotypes.[48]

Currently, multiple candidate vaccines are in clinical development and 1 vaccine, CYD-TDV (Dengvaxia), has recently been licensed in 19 countries, including Mexico, Brazil, El Salvador, and Paraguay. Dengvaxia is a tetravalent combination of 4 monovalent chimeric attenuated viruses with adequate protection against DENV3 and DENV4, modest protection against DENV1, and inadequate protection against DENV2.[49–51]

In 2011, the vaccine underwent phase III clinical trials, including more than 30 000 individuals in 10 endemic countries throughout Asia and Latin America. Pooled data indicated a 59.2% efficacy against all clinically diagnosed dengue cases, and 76.9% efficacy against severe dengue 1 year after a 3-dose vaccine regimen. In May 2016, the PAHO Technical Advisory Group stated that there was insufficient safety and effectiveness evidence to recommend the introduction of the DENV vaccine into routine national immunization programs of the region.[52] In November 2017, the vaccine manufacturer announced study results that showed increased hospitalized cases with severe dengue observed in young children from 2 to 5 years of age who were DENV-naïve.[53–55] On the basis of these findings, in April 2018, the WHO Scientific Advisory Group of Experts recommended conducting serologic testing of DENV immune status before vaccine administration and avoiding vaccinating DENV-naïve individuals.[56]

Two other live-attenuated DENV vaccines are in phase III trials, whereas still others, such as a purified inactivated vaccine, are in phase I trials. In addition, attenuated strains are being used as challenge strains in the human DENV infection model and have great promise for moving to phase III clinical trials.[53] DENV E protein is being pursued as the main antigen in several subunit-based vaccines.[53] Research on plant-based vaccines will potentially revolutionize the way vaccine can be produced, if proven successful.[57]

Other Arboviral Vaccines

Zika vaccines in the pipeline. ZIKV vaccine development has benefited from the head start that DENV research has provided. As with DENV, ZIKV also presents some human immunologic challenges for vaccine development. In many areas affected by ZIKV, seropositivity for DENV is very high. Although ZIKV differs from DENV by 41% to 46% in the genetic sequence of its envelope protein, some experts argue that the data suggest that cross-reactivity between DENV with ZIKV may drive antibody-dependent enhancement of infection in people previously exposed to DENV who are later infected with ZIKV.[58] Several vaccine platforms are being investigated for ZIKV vaccine development. Leading vaccine candidates, some of which are in phase I and II human trials, have produced promising results in preclinical studies.[59] Future challenges for ZIKV vaccine development include having sufficient cases to enable successful phase III trials.

Chikungunya vaccines in the pipeline. After the reemergence of CHIKV in 2004, there was renewed interest in developing a vaccine. Options including virus-like particles, subunit vaccines, vectored or chimeric vaccines, nucleic acid vaccines, and live attenuated vaccines have all been explored as possibilities. One significant challenge is that there are numerous different virus strains used, different animal models with different routes of both vaccination and challenge, and different methods for evaluating efficacy.[2]

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