Fig 1.
Overview of article selection in literature search.
Overview of the selection process of articles that study arbovirus antibody cross-reactivity in humans. Only studies with at least one vaccinee study group or one or more PCR or virus isolation confirmed sample sets were used in this systematic review (N = 102) (A). Studies were subdivided into 1082 individual data sets with different characteristics to assess cross-reactivity (B). Individual data sets were further subdivided to illustrate different residence and travel areas of included studies (N = 1836) (C). *Reasons for exclusion were not studying arbovirus cross-reactivity in humans and/or not describing serological cross-reactivity in sufficient detail (e.g., describing the specific viruses assessed for cross-reactive binding).
Fig 2.
Principle of scoring the reliability of cross-reactivity signals.
True cross-reactivity is defined as the combination of a high diagnostic certainty (diagnostic specificity score), a low chance of bias by possible previous arbovirus exposures (arbovirus background score) together with a large study size (study size score). Study data sets considered reliable regarding the serological cross-reactivity signals were selected for analyzing cross-reactivity.
Table 1.
Reliability scoring system categories and variables used for scoring.
Principles of scoring are based on either WHO or CDC recommendations [65–69], literature or were defined by the study team. For details see Supplemental Information A in S1 Appendix.
Fig 3.
Overview of studies providing information on multi-antigen antibody-reactivity testing.
Overview of all the combinations for which antibody measurements were done. Colours depict what the exposure had been for individuals sampled for serology testing (specified in the legend and the inner circle of the figure, ordered by serogroup), and the labels above each bar describe the virus antigens included in (cross-)reactivity panels. Total N is 1082 studies. Barmah forest (B), Semliki Forest (Se), Venezuelan equine encephalitis (V), Phlebovirus fever (P), Japanese encephalitis (J), Mammalian tick-borne (M), Yellow fever (Y), Japanese encephalitis, Mammalian tick-borne, Yellow Fever (JMY), Dengue (D), Spondweni (Sp).
Fig 4.
Overview of the geographic distribution of residence areas and travel destinations.
Overview of all residence areas of studied individuals and travel destinations of travellers of the included studies (N = 1836). Residence areas of vaccinees or patients that did not have any (reported) prior travel and therefore (likely) acquired infection at the residence area are depicted in red (N = 1383). For travellers that likely got infected at the travel destination, residence areas are shown in green (N = 453) and the travel destinations in blue (N = 453). Study frequency is depicted by size and the continents are coloured using a grey-scale. Figure is made using the R package maps and Natural Earth (Cultural base layer, medium scale, countries). The world map, is made using the world data base of the R package maps: https://www.rdocumentation.org/packages/maps/versions/3.4.0.
Fig 5.
Overview of scoring results and total reliability of studies.
Overview of scoring results of each category (diagnostic specificity, arbovirus background, study size) and total reliability for all included studies (N = 1082) ordered by publication date (oldest publication (left) to the most recent (right)). Scores of variables are divided into highest (red), high (orange), middle (dark blue), low (light blue) and lowest (light grey), whereby a high score indicates a low chance of bias and a low score a high chance of bias. The possible options for scoring can vary between variables (see legends per variable). Studies scoring highest on type of test and confirmation (studies with vaccinees or patients confirmed by PCR) are not evaluated for the other variables of the diagnostic specificity score weighing the serological diagnostic evidence (NA, dark grey). Total scores of each category are shown in four groups ranging from high to low: A (dark green), B (light green), C (yellow), D (light grey). The total composite reliability score of the studies is shown at the bottom ranging from highest (Group 1) to lowest (Group 5) in yellow, turquoise, dark blue, purple and pink, respectively.
Fig 6.
Distribution of (sub)category scores and total reliability groups.
Scores per individual variable of each category and total reliability groups of all studies scored in the reliability scoring system. Color legend as in Fig 5. NR = information not reported (grey striped pattern), NS = information not sufficiently specified (grey dotted pattern). The number of studies (N) represents the number of subdivided data sets used to score each variable.
Fig 7.
Reliability of arbovirus cross-reactivity results mapped to antigenic distance.
Calculated percentage of cases exposed to different arboviruses for which (multi-)(cross-)reactive antibodies were found to viruses listed at the bottom of the panels. The heading of each panel depicts the arbovirus(es) of exposure. Coloured circles indicate the scoring from group 1 (highest) to 5 (lowest) (yellow, turquoise, dark blue, purple and pink, respectively). The transparency of the circles corresponds to the different options of calculated cross-reactivity percentages. The blue overlays depict which arboviruses tested for cross-reactivity are in the same serogroup as the arbovirus of exposure, whereas the dark grey overlays show which arboviruses are within the genus of the arbovirus of exposure. *YFV, TBEV, JEV represents all different combinations of two of these viruses or all.
Table 2.
A minimum standard for metadata regarding the studied individuals.
Table 3.
A minimum standard for metadata regarding the methods used to confirm the virus exposure, determine the prior infection history and test for antibody cross-reactivity.