Studies on Serological Cross‐Reaction in Sequential Flavivirus Infections

Abstract

Acute-and convalescent-phase sera from patients with dengue (DEN) hemorrhagic fever (DHF) and Japanese encephalitis (JE) that contained pre-existing flavivirus antibodies were tested for cross-reacting antibodies to DEN, JE and yellow fever (YF) viruses by a neutralization (N) test . A fourfold or greater rise in N antibody titer in the convalescent-phase was considered significant . Of 39 DHF cases, obtained at Chiang Mai University Hospital, Thailand, 15 (38.5%) showed a rise in DEN antibody titer, while another 15 (38.5%) showed a significant rise in both DEN and JE N antibody titers. On the other hand, eight (61.5%) of 13 JE cases obtained at the same Hospital , showed a significant rise in JE antibody titer, while two (15.4%) showed a significant rise in both DEN and JE antibody titers. Sucrose gradient centrifugation and fractionation of these two crossreactive JE sera revealed that IgM class antibody was specific for JE , while IgG class antibody was cross-reactive. Of three JE cases with pre-existing YF antibody obtained in Okinawa , Japan, two showed a significant rise in YF and JE antibodies. Both IgM and IgG class antibodies to YF virus were elevated. These results indicate that the cross-reactivity among flaviviruses in different subgroups (complexes), was observed quite often, even by the N test , in sequential flavivirus infection.Key words: Flaviviruses, Sequential infections, Cross-neutralization testThere are more than 60 flaviviruses , including Japanese encephalitis (JE), dengue (DEN) and yellow fever (YF) viruses, and contain crossreactive antigens which make serodiagnosis difficult (11 for review). This is especially true in the regions where two or more flaviviruses are prevalent . Among the serological tests, the neutralization (N) test is considered to be more specific than complement-fixation (CF), hemagglutination-inhibition (HI) and enzyme-linked immunosorbent assay (ELISA) (16 for review). On the basis of close relationship in cross-neutralization tests using hyperimmune polyclonal antisera, flaviviruses are divided into at least eight antigenic subgroups (complexes), where JE and DEN viruses are classified into different subgroups, while YF virus remains unassigned (I).In Japan, only one flavivirus , i.e. JE virus, has been prevailing and HI test or ELISA has been employed for serodiagnosis without problems. While in the Southeast Asian countries such as Thailand and Vietnam, JE and DEN viruses have been coexisting and the outbreaks caused by these viruses have taken place simultaneously in the rainy season (6). It has been reported that in the secondary DEN virus infection, the serotype of the causative virus of the recent infection could not be identified by N test because of the cross-reactions . It was possible only by virus isolation or detection of specific viral genomic sequence (13). Secondary DEN infection in previously immune individuals with another serotype of DEN virus elicits broadly

Detection of Anti-Yellow Fever Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever Vaccination

“…23,24 Finally, subsequent exposure to YF virus or a related flavivirus could have caused IgM antibodies to persist or reform after infection. 25 We did not, however, find a significant association between being YF IgM positive and potential subsequent flavivirus exposure (e.g., travel to a YF or dengue-endemic area or flavivirus vaccination).…”

Rapid serologic diagnosis of dengue virus infection using a commercial capture ELISA that distinguishes primary and secondary infections.

“…We found that 8% of the patients without acute flavivirus infection and 45% of those with acute JE had moderately elevated levels of IgG (sample:calibrator absorbance ratio Ͼ 1.0). 14,33,34 However, with the higher cut-off of 3.0, only 20% of those with JE and none of those without a recent flavivirus infection were positive for IgG. Most cases of JE can be differentiated from dengue virus infection on clinical grounds, although there may be unusual cases of dengue virus encephalopathy.…”

Dengue Associated Acute Encephalitis Syndrome Cases in Son La Province, Vietnam in 2014

“…Other studies have also noted that the antibodies from dengue-infected patients are cross reactive against other flaviviruses (23,24). Based on the data of the National Institute of Hygiene and Epidemiology in Vietnam, no DENV outbreak was reported in Son La Province during 2013-2014.…”