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.

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.

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.

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.

Travelling arboviruses: A historical perspective.

Chikungunya, dengue, yellow fever and Zika viruses share many attributes. All are complex and widespread zoonoses of subhuman primates that have made successful transitions to the urban Aedes aegypti transmission cycle. More important, they have an established record of travelling, having moved from their place of origin hundreds of years ago, sometimes repeatedly.

Dengue infection and advances in dengue vaccines for children.

Dengue viruses are endemic in most tropical and subtropical countries where they produce disease ranging from a mild fever to a severe, potentially fatal vascular permeability syndrome. We reviewed the status of development and testing in children of three vaccines designed to protect against the four dengue viruses. The first dengue virus vaccine, Dengvaxia, now licensed in 20 endemic countries, the EU and the USA, provides protection against severe dengue in seropositive individuals but increases the risk for naive recipients to develop severe dengue and to be hospitalised.

A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice.

Dengue viruses cause severe and sudden human epidemics worldwide. The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. Here, we reverse engineered the T164S mutation of NS1, associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain.

Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine.

A tetravalent live-attenuated 3-dose vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (CYD, also called Dengvaxia) completed phase 3 clinical testing in over 35,000 children leading to a recommendation that vaccine be administered to >/ = 9 year-olds residing in highly dengue- endemic countries. When clinical trial results were assessed 2 years after the first dose, vaccine efficacy among seropositives was high, but among seronegatives efficacy was marginal. Breakthrough dengue hospitalizations of vaccinated children occurred continuously over a period of 4-5 years post 3rd dose in an age distribution suggesting these children had been vaccinated when seronegative.

Dengvaxia sensitizes seronegatives to vaccine enhanced disease regardless of age.

During a large scale clinical efficacy trial of the Sanofipasteur live-attenuated tetravalent dengue vaccine (Dengvaxia), features of hospitalized disease accompanying dengue infections in placebo recipients were closely similar to those in vaccinated children. However, the age specific hospitalization curves for these two populations differed. The curve for children vaccinated at ages 2-16 years closely resembled the 1981 age specific hospitalization rate curve for Cuban children infected with DENV 2 who were sensitized by a prior DENV 1 infection.

Use of the live attenuated Japanese Encephalitis vaccine SA 14-14-2 in children: A review of safety and tolerability studies.

Japanese encephalitis (JE) is the leading cause of viral neurological disease and disability in Asia. Some 50-80% of children with clinical JE die or have long-term neurologic sequelae. Since there is no cure, human vaccination is the only effective long-term control measure, and the World Health Organization recommends that at-risk populations receive a safe and effective vaccine.

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? There Is Only One True Winner.

The scientific community now possesses information obtained directly from human beings that makes it possible to understand why breakthrough-enhanced dengue virus (DENV) infections occurred in children receiving Sanofi Pasteur's Dengvaxia tetravalent live attenuated vaccine and to predict the possibility of breakthrough-enhanced DENV infections following immunization with two other tetravalent live attenuated vaccines now in phase III testing. Based upon recent research, Dengvaxia, lacking DENV nonstructural protein antigens, did not protect seronegatives because it failed to raise a competent T-cell response and/or antibodies to NS1. It is also possible that chimeric structure does not present the correct virion conformation permitting the development of protective neutralizing antibodies.

Achieving safe, effective, and durable Zika virus vaccines: lessons from dengue.

Newly proposed candidate Zika virus vaccines might or might not succeed in raising safe, effective, and durable protection against human Zika virus infections or syndromes. Analyses of a clinically tested and licensed dengue vaccine that failed to protect seronegative individuals from breakthrough or enhanced dengue infections suggest that poor T-cell immunity might have contributed to protection failure. Because of the similarity of Zika and dengue viruses, an analogous unwanted outcome might occur with some Zika virus vaccine designs.

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.