Dataset Information

Neutralizing antibodies from prior exposure to dengue virus negatively correlate with viremia on re-infection.

ABSTRACT:

Background

India is hyperendemic to dengue and over 50% of adults are seropositive. There is limited information on the association between neutralizing antibody profiles from prior exposure and viral RNA levels during subsequent infection.

Methods

Samples collected from patients with febrile illness was used to assess seropositivity by indirect ELISA. Dengue virus (DENV) RNA copy numbers were estimated by quantitative RT-PCR and serotype of the infecting DENV was determined by nested PCR. Focus reduction neutralizing antibody titer (FRNT) assay was established using Indian isolates to measure the levels of neutralizing antibodies and also to assess the cross-reactivity to related flaviviruses namely Zika virus (ZIKV), Japanese encephalitis virus (JEV) and West Nile virus (WNV).

Results

In this cross-sectional study, we show that dengue seropositivity increased from 52% in the 0-15 years group to 89% in >45 years group. Antibody levels negatively correlate with dengue RNAemia on the day of sample collection and higher RNAemia is observed in primary dengue as compared to secondary dengue. The geometric mean FRNT₅₀ titers for DENV-2 is significantly higher as compared to the other three DENV serotypes. We observe cross-reactivity with ZIKV and significantly lower or no neutralizing antibodies against JEV and WNV. The FRNT₅₀ values for international isolates of DENV-1, DENV-3 and DENV-4 is significantly lower as compared to Indian isolates.

Conclusions

Majority of the adult population in India have neutralizing antibodies to all the four DENV serotypes which correlates with reduced RNAemia during subsequent infection suggesting that antibodies can be considered as a good correlate of protection.

SUBMITTER: Anantharaj A

PROVIDER: S-EPMC10587183 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Neutralizing antibodies from prior exposure to dengue virus negatively correlate with viremia on re-infection.

Anantharaj Anbalagan A Agrawal Tanvi T Shashi Pooja Kumari PK Tripathi Alok A Kumar Parveen P Khan Imran I Pareek Madhu M Singh Balwant B Pattabiraman Chitra C Kumar Saurabh S Pandey Rajesh R Chandele Anmol A Lodha Rakesh R Whitehead Stephen S SS Medigeshi Guruprasad R GR

Communications medicine 20231019 1

<h4>Background</h4>India is hyperendemic to dengue and over 50% of adults are seropositive. There is limited information on the association between neutralizing antibody profiles from prior exposure and viral RNA levels during subsequent infection.<h4>Methods</h4>Samples collected from patients with febrile illness was used to assess seropositivity by indirect ELISA. Dengue virus (DENV) RNA copy numbers were estimated by quantitative RT-PCR and serotype of the infecting DENV was determined by ne ...[more]

PMID: 37857747

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Project description:UnlabelledSevere dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fcγ receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and in vivo disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized in vitro promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF-α) Abs. Flow cytometric analysis identified increased infection in CD11b(int) CD11c(int/hi) CD103(-) antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-α production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics.ImportanceWe examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-α-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies.

Dataset Information

Neutralizing antibodies from prior exposure to dengue virus negatively correlate with viremia on re-infection.

Background

Methods

Results

Conclusions

Publications

Neutralizing antibodies from prior exposure to dengue virus negatively correlate with viremia on re-infection.

Similar Datasets

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