Better Understanding Dengue Dynamics: How Long Does Immunity Last?

Immunity to dengue might not be as long-lasting as thought but rather decreases over time. This is the conclusion of an important study for the development of dengue vaccines in endemic areas.

[This text has been written by Xavier Rodó, head of th ISGlobal Climate & Health programme, and Leonardo López, postdoctoral fellow of the programme.]

Dengue is still a major public health problem in tropical areas and is projected to become a significant risk in temperate countries where mosquito vectors are gaining geographical expansion. The development of a dengue vaccine able to provide full protection against risk of severe clinical illness still remains the desired solution to significantly reduce the burden of the disease. However, current implemented or trialled vaccines are only partly effective.

We analysed more than 20 years of data from French Polynesia and found that immunity to dengue virus (DENV) can be imperfect and potentially even wane over time. Even partially effective vaccines, if against all 4 viral serotypes, may be of public health value, as they could prevent immunity waning and confer protection against severe disease in at-risk previously exposed age groups. In our COVID-19 redesigned world, where partially effective vaccines are promoted to everybody to protect at-risk individuals (the elderly or people with co-morbidities), using similar strategies to combat dengue should be considered.

Dengue Fever: A Global Epidemic Explained

Usual Suspects: 002 Aedes Mosquito

Life-long Serotype-Specific Immunity in Dengue Infection May Not Always Occur

The dengue virus is caused by four different viral serotypes (DENV-1, DENV-2, DENV-3 y DENV-4). Dengue Virus types have a similar envelope or E proteins so, during infection, cross-reactive (heterotypic) antibodies against all DENV types are produced. DENV types are immunologically distinct and induce the production of type-specific antibodies (homotypic).

Figure 1: Different types of DENV envelope proteins.

When an individual is re-infected with the same DENV type, then, memory B cells recognize it and will start to divide, resulting in the production of new B cells that make homotypic IgG and memory cells. When this happens, the antibody can eliminate DENV so quickly that the person does not become noticeably ill. When a person has a second DENV infection with a new DENV type, the primary responsibility is to make heterotypic antibodies against cross-reactive antigens to the first DENV type. This process is called ‘original antigenic sin’. Memory B cells are responsible for the production of these heterotypic antibodies. Virgin B cells will also produce homotypic antibodies against the infecting DENV type during this second exposure.

One important problem is that this pathway is not 100 percent true in all cases and life-long serotype-specific immunity following dengue virus infection may not always occur. Additionally, the true extent of this effect is unknown. Not only are dengue virus serotypes not so immunologically segregated as thought, but also sterilizing serotype-specific immunity may not always follow infection.

French Polynesia. Photo: PxHere.

Considering Waning Immunity to Better Explain Dengue Dynamics

An analysis of more than 20 years of monotypic epidemics in the isolated French Polynesian islands revealed that while the risk of symptomatic dengue infection did conform to the classical paradigms of homotypic immunity and increased disease risk in heterotypic secondary infections, incorporation of waning immunity improved the ability of epidemiological models to capture the observed epidemic dynamics. Not only this shows how the inclusion of waning immunity into population-based models can reveal essential facets of the immune response to natural dengue virus infection, but it also has significant ramifications for vaccine development and implementation in dengue-endemic areas.

In contrast to other endemic settings, French Polynesia, an isolated group of islands in the South Pacific (See Figure 2) has recorded 15 mono-serotype dengue epidemics of all four serotypes since 1944 and offered a simpler but also a unique epidemiological setting to examine the immuno-epidemiology of dengue. From our 35−year database of laboratory-confirmed geolocated cases with age and gender (1979–2014), seven monotypic and one multi-typic epidemic occurred, followed for the most part by long periods of low-level inter-epidemic transmission (See panel B of Figure 2). Through analysis of consecutive epidemics over this 35−year period and implementation of novel dynamical models, this work assesses the evidence supporting the classical dengue paradigms, evaluates the epidemiological importance of asymptomatic infections, and addresses the role of waning homotypic immunity.

Figure 2: The age distribution (A), time series of DENV strains (B), and island connections (C).

What We Bring to Dengue Research

Our work suggests that by incorporating loss of immunity parameters into a classic population-based model, the improvements in modeling epidemiological profiles are significant. In particular, the inclusion of asymptomatic and re-susceptibility parameters can reveal fundamental immunological characteristics of responses to infection. They may offer a robust alternative to characterizing the broad dengue epidemiological picture when serological data are lacking, and whenever available data does not provide clear information on protection and sensitivity to viral variation.