Long-Term Kinetics of Serological Antibodies against Vibrio cholerae Following a Clinical Cholera Case: A Systematic Review and Meta-Analysis

Abstract

Background: Approximately 2.9 million people worldwide suffer from cholera each year, many of whom are destitute. However, understanding of immunity against cholera is still limited. Several studies have reported the duration of antibodies following cholera; however, systematic reviews including a quantitative synthesis are lacking.

Objective: To meta-analyze cohort studies that have evaluated vibriocidal, cholera toxin B subunit (CTB), and lipopolysaccharide (LPS) antibody levels following a clinical cholera case.

Methods: Design: Systematic review and meta-analysis. We searched PubMed and Web of science for studies assessing antibodies against Vibrio cholerae in cohorts of patients with clinical cholera. Two authors independently extracted data and assessed the quality of included studies. Random effects models were used to pool antibody titers in adults and older children (aged ≥ 6 years). In sensitivity analysis, studies reporting data on young children (2-5 years) were included.

Results: Nine studies met our inclusion criteria for systematic review and seven for meta-analysis. The pooled mean of vibriocidal antibody titers in adults and older children (aged ≥ 6 years) was 123 on day 2 post-symptom onset, which sharply increased on day 7 (pooled mean = 6956) and gradually waned to 2247 on day 30, 578 on day 90, and 177 on day 360. Anti-CTB IgA antibodies also peaked on day 7 (pooled mean = 49), followed by a rapid decrease on day 30 (pooled mean = 21), and further declined on day 90 (pooled mean = 10), after which it plateaued from day 180 (pooled mean = 8) to 360 (pooled mean = 6). Similarly, anti-CTB IgG antibodies peaked in early convalescence between days 7 (pooled mean = 65) and 30 (pooled mean = 69), then gradually waned on days 90 (pooled mean = 42) and 180 (pooled mean = 30) and returned to baseline on day 360 (pooled mean = 24). Anti-LPS IgA antibodies peaked on day 7 (pooled mean = 124), gradually declined on day 30 (pooled mean = 44), which persisted until day 360 (pooled mean = 10). Anti LPS IgG antibodies peaked on day 7 (pooled mean = 94). Thereafter, they decreased on day 30 (pooled mean = 85), and dropped further on days 90 (pooled mean = 51) and 180 (pooled mean = 47), and returned to baseline on day 360 (pooled mean = 32). Sensitivity analysis including data from young children (aged 2-5 years) showed very similar findings as in the primary analysis.

Conclusions: This study confirms that serological antibody (vibriocidal, CTB, and LPS) titers return to baseline levels within 1 year following clinical cholera, i.e., before the protective immunity against subsequent cholera wanes. However, this decay should not be interpreted as waning immunity because immunity conferred by cholera against subsequent disease lasts 3-10 years. Our study provides evidence for surveillance strategies and future research on vaccines and also demonstrates the need for further studies to improve our understanding of immunity against cholera.

Keywords: antibodies; cholera; cholera toxin B; immunity; immunoglobulin; lipopolysaccharide; vibriocidal; waning.

Figure 1

(A) Forest plots of the kinetics of vibriocidal antibody titers after cholera [37,39,40,42,43]. (B) Kinetics of vibriocidal antibody titers after cholera.

Figure 1

(A) Forest plots of the kinetics of vibriocidal antibody titers after cholera [37,39,40,42,43]. (B) Kinetics of vibriocidal antibody titers after cholera.

Figure 2

(A) Forest plots of the kinetics of anti-cholera toxin B subunit IgA following cholera [37,38,39,40,42,43]. (B) Kinetics of anti-cholera toxin B subunit IgA following cholera.

Figure 2

(A) Forest plots of the kinetics of anti-cholera toxin B subunit IgA following cholera [37,38,39,40,42,43]. (B) Kinetics of anti-cholera toxin B subunit IgA following cholera.

Figure 3

(A) Forest plots of the kinetics of anti-cholera toxin B subunit IgG following cholera [37,38,39,40,42,43]. (B) Kinetics of anti-cholera toxin B subunit IgG following cholera.

Figure 3

(A) Forest plots of the kinetics of anti-cholera toxin B subunit IgG following cholera [37,38,39,40,42,43]. (B) Kinetics of anti-cholera toxin B subunit IgG following cholera.

Figure 4

(A) Forest plots of the kinetics of anti-lipopolysaccharide IgA following cholera [37,38,39,40,42]. (B) Kinetics of anti-lipopolysaccharide IgA following cholera.

Figure 4

(A) Forest plots of the kinetics of anti-lipopolysaccharide IgA following cholera [37,38,39,40,42]. (B) Kinetics of anti-lipopolysaccharide IgA following cholera.

Figure 5

(A) Forest plots of the kinetics of anti-lipopolysaccharide IgG following cholera [37,38,39,40,42]. (B) Kinetics of anti-lipopolysaccharide IgG following cholera.

Figure 5

(A) Forest plots of the kinetics of anti-lipopolysaccharide IgG following cholera [37,38,39,40,42]. (B) Kinetics of anti-lipopolysaccharide IgG following cholera.