Studies on Serological Cross‐Reaction in Sequential Flavivirus Infections

Yoshihiro Makino; Masayuki Tadano; Mika Saito; Niwat Maneekarn; Nopporn Sittisombut

doi:10.1111/j.1348-0421.1994.tb02152.x

Studies on Serological Cross‐Reaction in Sequential Flavivirus Infections

Yoshihiro Makino, Masayuki Tadano, Mika Saito, Niwat Maneekarn, Nopporn Sittisombut, Virat Sirisanthana, Boosom Poneprasert, T. Fukunaga

Wiley (1994) • Volume 38, Issue 12, Pages 951-955

Empirical-ClinicalCaseSeriesPDF AvailableGrade Eligible⚠️ Moderate Risk Flags

Overall Assessment

Weak Methodological Quality

Assessment created by PaperScorers Medical AI v0.1.0 on Jan 13, 2026

D-

38/100

Key Takeaways

•Cross-neutralisation across flavivirus complexes is common in sequential infections.
•In DHF cases, 38.5% showed DEN-only rises; another 38.5% showed DEN+JE rises.
•JE cases: 61.5% had JE-only rises; some had DEN+JE rises; one dengue encephalopathy suspected.
•IgM was virus-specific (JE), IgG cross-reactive; YF-vaccinated JE cases showed rises to YF and JE in IgM/IgG.

Conclusion

Neutralisation tests alone can misidentify causative flaviviruses in sequential infections; combining RT-PCR/virus isolation and IgM-focused assays improves diagnostic specificity.

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Quality Dimensions

Bias & Integrity

COI handling, outcome switching, selective reporting

D45

Methods Rigour

Protocol clarity, sampling, controls

D48

External Validity

Generalisability, setting, population

D-35

Transparency & Reproducibility

Data/code/materials availability, preregistration

F10

Significance & Novelty

Contribution vs prior art; context if known

C-55

Statistical Validity

Models, assumptions, multiplicity, CI priority

D-35

Integrity & Transparency

Integrity checks

P-hacking risk?

?

None suspected

Signs of selective hypothesis testing or analysis choices that could inflate false positive rates.

Outcome switching?

?

None suspected

Evidence that primary outcomes were changed during or after the study, potentially distorting results.

Conflict of interest?

?

Review recommended

Authors have financial or other relationships that could bias research findings.

Data integrity issues?

?

None suspected

Concerns about the accuracy, completeness, or authenticity of the reported data.

Open science signals

Research data

?

Not shared

Raw data used in the analyses is publicly available or accessible upon request.

Analysis code

?

Not shared

Code or scripts used to analyze the data are shared for reproducibility.

Study materials

?

Not shared

Protocols, questionnaires, and other materials are publicly available.

Premise

Primary Research Question

How frequently do cross-neutralising antibodies arise across flavivirus complexes in sequential infections, and which Ig classes drive this?

Hypothesis

Cross-reactivity occurs often in sequential infections; IgM is more specific while IgG is cross-reactive.

Hypothesis is Falsifiable

✓Yes

Fourfold titre-rise thresholds and class-separated assays enable falsification.

PICO Framework

Population✓Yes

DHF and JE patients; 1991 Chiang Mai; 3 JE in Okinawa with prior YF vaccine.

Intervention—Not specified

No intervention; observational serology.

Comparison—Not specified

No comparator arm; descriptive case series.

Outcome✓Yes

Rise in neutralisation titres and class-specific responses are clinically relevant for diagnosis.

Literature Positioning

Literature Review Balanced

Well covered

Background on flavivirus cross-reactivity and tests with appropriate citations.

Evidence: pp. 951–952, refs 1,11,16

Research Gap Clearly Stated

Well covered

Notes detailed studies in flavivirus sequential infection not yet done.

Evidence: p. 952: “detailed studies… have not yet done.”

Stated Contribution Clear

Well covered

Quantifies cross-reactivity in paired sera and IgM vs IgG class behaviour.

Evidence: pp. 953–954 results; IgM/IgG fractionation

Study Provenance

Peer reviewed venueGrant funding disclosedConflict disclosure provided5 affiliations listed

Authors & Affiliations

Univ. of the Ryukyus, Okinawa, Japan; Chiang Mai University, Thailand (p. 951).

Funding Statement

Supported by Japanese Ministry of Science and Ministry of Health and Welfare grants (p. 954).

Conflicts of Interest

Not stated.

Peer Review

✓Peer‑reviewed journal article in Microbiol. Immunol. 1994.

Evidence: p. 951 journal header

Methodological Assessment

Observational StudySTROBEObservational

4 applicable checklist items.

Yes 3 · No 1

Study Design & Definitions

✓

Participant Selection Described

Patient selection (hospital, year, diagnoses) described.

Evidence: p. 952: 39 DHF, 13 JE; Chiang Mai 1991; +3 Okinawa JE.

✓

Variable Definitions Clear

Fourfold rise threshold; viruses/assays defined.

Evidence: p. 952: “fourfold or greater” N test; virus strains listed.

Bias Mitigation

✗

Selection Bias Addressed

Selection bias not discussed; convenience hospital sample.

Evidence: pp. 952–953; no bias discussion.

✓

Misclassification Assessed

Misclassification probed via RT-PCR and virus isolation triangulation.

Evidence: p. 952; Table 1 summary on p. 953.

Modules without applicable checklist items (9)

These designs were fully marked as not applicable but remain available for reference.

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 cross‐reactive 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.

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Study Overview

Study Design

Case Series

Primary classification used to evaluate this research.

Population

Patients with clinical DHF or JE at Chiang Mai University Hospital (Thailand, 1991) and 3 JE cases in Okinawa with prior YF vaccination.

Brief summary of who or what was studied.

Sample Size

55

Number of participants included in the study analyses.

Pre-registration

Not registered

Indicates whether the protocol or trial was registered before data collection.

Follow-up

Paired sera: acute 2–6 days vs convalescent 6–46 days after illness onset.

Duration of observation or follow-up for outcomes.

Primary Outcome

Unclear whether the primary outcome was pre-specified.

Effect Size

proportion: DHF: 38.5% DEN-only rise; 38.5% DEN+JE rise (15/39 each). JE: 61.5% JE-only rise (8/13).

Reviewer Notes

Descriptive case series of paired sera; outcomes are fourfold rises in neutralisation titres and cross-reactivity patterns.

Publication Details

DOI

10.1111/j.1348-0421.1994.tb02152.x

Published

December 1, 1994

Citations

103 citations

FWCI

0.54

External Resources

DOI Link OpenAlex

Disclaimer: This assessment is generated by AI and should not be the sole basis for clinical or research decisions. Always review the original paper and consult with domain experts.

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