Dengue Vaccine: A Double-Edged Sword

Introduction

Dengue virus (DENV), amongst other arthropod-borne flaviviruses, poses the most significant health threat to the global community. ^1-3 It comprises four antigenically distinct serotypes (1-4) and causes diseases ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). ^4,5 Approximately more than 2.5 billion people in over 100 countries are at risk of dengue infection, with several hundred thousand cases of life threatening DHF/DSS occurring every year. ⁶ Due to the increasing number of DENV infections worldwide, the development of an effective vaccine remains a global health priority as there is currently no vaccine available against dengue. ⁷

Notably, the development of various dengue vaccine candidates is already making good progress. ^7,8 These include live-attenuated, inactivated virus, protein-subunit and DNA vaccines. Generally, an ideal vaccine should be free from significant reactogenicity and able to induce strong and equal lifelong protection against all four serotypes of DENV. ⁷ It is not acceptable if the immune response generated by the vaccine wanes below protective levels over time and as a result, contributes to the enhancement of the disease. However, the indicators that can be used to correlate safety and risk of such vaccines have yet to be established.

As the development of a dengue vaccine opens an arena of uncertainties, it can be described as Pandora's box of mixed good and detrimental results. This is because dengue, unlike other diseases, presents a unique case against the use of vaccines: a poorly developed dengue vaccine may enhance the disease, rather than prevent it.

Table 1.

Understanding Potential Risks Associated with DENV Vaccines

One major challenge unique to DENV vaccine development is the potential risk of antibody-dependent enhancement (ADE) of disease ⁹ (Table 1). It is believed that vaccination of an individual against a mono-serotype of DENV may predispose the person to ADE due to the presence of non-neutralising antibodies that can opsonise the infection. ^7,10,11 Therefore, it is proposed that vaccination using a tetravalent DENV vaccine formulation can reduce the risk of ADE because the multi-epitopes present on the vaccine can generate adequate protection against all serotypes of DENV infection. ^7,12 However, the safety and efficacy of the tetravalent vaccine cannot be proven due to the lack of a suitable animal model for DENV research. ⁹ Generally, laboratory animals do not produce the whole spectrum of disease during challenge by DENV. ^13-16 Furthermore, there are also limitations regarding the use of tetravalent forms of the vaccine, as discussed below.

According to the theory of multi-hit mechanism of neutralisation, a minimal threshold antibody titre is required in order for neutralisation to occur.17,18 Thus, it is possible that protective antibody titre may wane over an extended period of time after vaccination, drop below threshold level and become sub-neutralising against the virus. Based on the principle of ADE, enhancement of disease may occur at this stage. Therefore, even for tetravalent vaccination, subsequent vaccine boosts are required to ensure lifelong protection of individuals and eliminate the harm of disease enhancement due to waning antibody levels.

There are also possible safety risks related to the vaccine formulation. Currently, major efforts are focused on the development of live-attenuated vaccines. ⁷ However, managing viral interference and balancing attenuation to produce acceptable immunogenicity with minimal risks of reactogenicity is a challenge. According to a case study by Kitchener and colleagues, ¹⁹ a Phase-1b trial was performed on adult volunteers to assess the immunogenicity and safety of two live-attenuated tetravalent dengue vaccines. The vaccine trial was stopped prematurely due to adverse reactogenicity of the adult volunteers against the vaccine. Mild dengue-like symptoms and severe rash were observed. Formulation issues related to the DENV3 vaccine were blamed for the failed trial.

Significantly, incidences of reversion to virulence have been observed in other infectious disease models, such as the outbreaks of vaccine-derived polio virus due to the use of the oral poliovirus vaccine. ^20-22 Adverse...