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. 2023 Dec 15;11(12):1857.
doi: 10.3390/vaccines11121857.

A Novel, Comprehensive A129 Mouse Model for Investigating Dengue Vaccines and Evaluating Pathogenesis

Mya Myat Ngwe Tun  1   2   3 , Khine Mya Nwe  2 , Jean Claude Balingit  1 , Yuki Takamatsu  1   2 , Shingo Inoue  4 , Basu Dev Pandey  5 , Takeshi Urano  3 , Michinori Kohara  6 , Kyoko Tsukiyama-Kohara  7 , Kouichi Morita  1   2   5
Affiliations

A Novel, Comprehensive A129 Mouse Model for Investigating Dengue Vaccines and Evaluating Pathogenesis

Mya Myat Ngwe Tun et al. Vaccines (Basel). .

Abstract

In search of a mouse model for use in evaluating dengue vaccines, we assessed A129 mice that lacked IFN-α/β receptors, rendering them susceptible to dengue virus (DENV) infection. To our knowledge, no reports have evaluated dengue vaccine efficiency using A129 mice. A129 mice were given a single intraperitoneal (IP) or subcutaneous (SC) injection of the vaccine, Dengvaxia. After 14 days of immunization via the IP or SC injection of Dengvaxia, the A129 mice exhibited notably elevated levels of anti-DENV immunoglobulin G and neutralizing antibodies (NAb) targeting all four DENV serotypes, with DENV-4 displaying the highest NAb levels. After challenge with DENV-2, Dengvaxia and mock-immunized mice survived, while only the mock group exhibited signs of morbidity. Viral genome levels in the serum and tissues (excluding the brain) were considerably lower in the immunized mice compared to those in the mock group. The SC administration of Dengvaxia resulted in lower viremia levels than IP administration did. Therefore, given that A129 mice manifest dengue-related morbidity, including viremia in the serum and other tissues, these mice represent a valuable model for investigating novel dengue vaccines and antiviral drugs and for exploring dengue pathogenesis.

Keywords: A129 mouse; Dengvaxia vaccine; dengue virus; neutralization antibody; viral loads.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of the generation of immune serum, and the challenge with DENV-2 involved in the A129 mouse model. A129 mice were immunized either intraperitoneally or subcutaneously with a single dose of Dengvaxia or PBS. After vaccination, serum samples were collected on days 0 and 14 for antibody detection and mice were then challenged with the DENV-2 virus. Other activities are indicated in the diagram above.
Figure 2
Figure 2
(A) Anti-DENV IgG responses to mock-immunized (n = 10), intraperitoneally immunized (n = 10), and subcutaneously immunized (n = 10) A129 mice at days 0 and 14. Immunized mice were given a single dose of Dengvaxia at day 0. (B) Neutralization antibody titers against four DENV serotypes on the 14th day after immunization of mice with Dengvaxia via intraperitoneal (n = 10) and subcutaneous (n = 10) administration. A comparison between two groups was performed using the Mann–Whitney U test. All comparisons among the neutralization antibody titers against four serotypes of DENV were performed using the Kruskal–Wallis test. p-value < 0.05 was considered statistically significant.
Figure 3
Figure 3
(A) Survival rate and (B) body weight change (%) in the three groups of A129 mice after challenge with DENV-2 (5 × 105 FFU/mouse). The three groups were Dengvaxia IP (n = 5), Dengvaxia SC (n = 5), and the virus control (n = 5). The body weights of the mice were monitored daily at the same time and recorded as a percentage of initial body weight. Student’s t test was used to analyze the body weight change between the two groups of mice. A p value < 0.05 was considered statistically significant.
Figure 4
Figure 4
Viremia levels of serum (RNA copies/mL) in individual mice of the three groups of A129 mice after DENV-2 (5 × 105 FFU/mouse) challenge. The three groups were Dengvaxia IP (n = 5), Dengvaxia SC (n = 5), and the virus control (n = 5) groups. A comparison between two groups was performed using the Mann–Whitney U test. A p-value < 0.05 is considered statistically significant.
Figure 5
Figure 5
Viral load (RNA copies/g of tissue) in each tissue/organ of individual mice from the three groups of A129 mice 5 days post-infection with DENV-2 (5 × 105 FFU/mouse). The three groups were Dengvaxia IP (n = 5), Dengvaxia SC (n = 5), and the virus control (n = 5) groups. A comparison between two groups was performed using the Mann–Whitney U test. A p value < 0.05 was considered statistically significant.
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