Helminth infection is linked to an impaired neutralisation response to SARS-CoV-2 post vaccination

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McCormack, Louis Banda, Stephen Kasenda, Lyson Samikwa, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9305049/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Chronic helminth infections can modulate immune responses to infection and vaccination. This study explored the association between current helminth infection, including waterborne and soil-transmitted helminths (STHs), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody (nAb) responses. Samples were collected cross-sectionally from participants across rural (Karonga) and urban (Lilongwe) regions in Malawi. Helminth infections were detected via real-time PCR in stool and urine samples, targeting Schistosoma spp., Ascaris lumbricoides , Ancylostoma duodenale , Necator americanus , and Trichuris trichiura . SARS-CoV-2 nAbs were measured using a human immunodeficiency virus (HIV) pseudotyped virus neutralisation assay. A nucleocapsid (N) protein enzyme linked immunosorbent assay (ELISA) identified prior natural SARS-CoV-2 infection in vaccinated participants. IgG targeting the spike (S) protein was measured using an ELISA. Helminth infection was found to be associated with reduced nAb responses post coronavirus disease 2019 (COVID-19) vaccination, but not after natural SARS-CoV-2 infection. IgG responses were also impaired among those helminth-infected. Generalised additive model analysis confirmed this interaction while considering covariates. This suggests that deworming before vaccination may improve responses in helminth endemic regions. Health sciences/Diseases Biological sciences/Immunology Health sciences/Medical research Biological sciences/Microbiology SARS-CoV-2 helminth neutralisation antibody vaccination Figures Figure 1 Figure 2 Figure 3 Introduction Chronic helminth infections are known to modulate host immune responses to vaccines and pathogens, including SARS-CoV-2 [ 1 ]. Helminth-induced immunoregulation may reduce COVID-19 severity by dampening hyperinflammatory responses [ 2 ], yet the same regulation may also weaken vaccine-induced immunity [ 1 ]. This is particularly relevant in sub-Saharan Africa, where helminth infections are endemic and may partly contribute to the comparatively lower burden of severe COVID-19 in the region. Mbow et al. [ 3 ] proposed that helminths promote IL-4–driven expansion of virtual memory T cells and reduce proinflammatory monocytes, thereby dampening cytokine storms and lung inflammation. Understanding these interactions is important for optimising COVID-19 control measures and vaccination strategies in helminth-endemic regions. However, evidence on helminth–SARS-CoV-2 interactions remains limited. Two studies in Ethiopia reported reduced COVID-19 severity among helminth-infected individuals [ 2 , 4 ], though neither examined SARS-CoV-2 antibodies. Other studies found no effect of infections with Ascaris lumbricoides , Opisthorchis viverrine, Onchocerca volvulus , or Trichinella spiralis on SARS-CoV-2 neutralising antibody (nAb) levels [ 5 – 8 ], although methodologies varied. The Ascaris , Onchocerca, and Trichinella studies used serology to infer helminth exposure rather than demonstrating active infection [ 5 , 7 , 8 ], while the Opisthorchis study measured active infection and reported reduced RBD-specific IgG levels in co-infected individuals [ 6 ]. One study observed impaired anti-SARS-CoV-2 S1 IgG responses in individuals with moderate or severe Schistosoma mansoni infection compared with those Kato-Katz negative [ 9 ], however they had very limited participants, and did not assess functional immunity. Additionally, a recent study in Ghana reported higher helminth seroprevalence among COVID-19 asymptomatic individuals and an associated shift toward Th2-type immune responses [ 10 ]. Here, we investigated whether current helminth infections as determined by real time PCR were associated with altered SARS-CoV-2 nAb responses in adults from rural and urban Malawi. These data provide insights into SARS-CoV-2 immunity in helminth-endemic settings and have implications for vaccination programmes. Methods Study population The study was conducted in Karonga (rural) and Lilongwe (urban, Area 25) (Supplementary Fig. 1), where Schistosoma spp. and soil-transmitted helminth (STH) are endemic [ 11 – 13 ]. We included 371 adults participating in a longitudinal SARS-CoV-2 serosurveillance cohort [ 14 ]. Samples were collected cross-sectionally between January and April 2022 with written, informed consent. Individuals with HIV were excluded due to known interference of antiretroviral therapy with the pseudotype neutralisation assay [ 15 ]. Sample collection and laboratory procedures Questionnaires captured demographic and clinical data (Supplementary Methods). Blood, stool and urine samples were collected. Serum was stored at − 80°C before transfer to the MRC-University of Glasgow Centre for Virus Research for SARS-CoV-2 neutralisation assays. Stool and urine samples were analysed at Kamuzu University of Health Sciences for helminth infection. Neutralisation against ancestral B.1, Beta, Delta, Omicron BA.1, and BA.2 variants (Supplementary Table 1), the predominant variants circulating in Malawi before sample collection [ 14 ], was measured using an HIV pseudotype-based assay. Vaccinated participants were tested for anti-nucleocapsid (N) IgG by ELISA to identify prior infection (Supplementary Methods). All participants were tested for anti-spike (S) IgG by ELISA to measure the overall IgG responses (Supplementary Methods). DNA extracted from stool and urine was tested by real-time PCR for Schistosoma spp., A. lumbricoides, Ancylostoma duodenale, Necator americanus , and Trichuris trichiura . Urine samples were tested for S chistosoma spp. (Supplementary Methods, Supplementary Table 2). Cycle threshold (Ct) values were used as a proxy for helminth infection intensity, with a lower Ct indicating higher intensity. Statistical analyses For prevalence percentages, 95% binomial confidence intervals (CI) were reported. A two-proportion chi-squared test (two-tailed) was used to compare prevalence between groups. For nAb titres, the median and interquartile range (IQR) were presented as the data were not normally distributed. The non-parametric two-tailed Wilcoxon rank-sum test was used to assess statistical differences in titres. A false discovery rate (Benjamini-Hochberg) correction was applied when making multiple individual comparisons to reduce false positivity, while maintaining statistical power for the small sample size. P-values < 0.05 were considered statistically significant, with very small p-values represented as p < 0.0001. Further statistical analyses methods that involved descriptive analysis of participants and effect size estimate methods, are described in the Supplementary Methods. Generalised additive models (GAMs) were used to evaluate predictors of nAb titres, including age, helminth infection status, vaccination, and time since vaccination (Supplementary Methods). Ethics declaration statement Ethical approval was obtained from the Malawi College of Medicine Research Ethics Committee (P11/20/3177, 11th December 2020), and the University of Glasgow (200200056, 8th February 2021). Results Participant characteristics Of 371 participants, 242 were from Karonga (rural) and 129 were from Lilongwe (urban). Median age was similar between sites (Karonga: 36.1 years, IQR 16.0–50.0 years; Lilongwe: 38.2 years, IQR 28.3–49.2 years; p = 0.49, Wilcoxon test) (Supplementary Table 3). A lower proportion of participants in Karonga were female (p = 0.002, 𝜒 2 test). COVID-19 vaccination coverage was 31.8% (95% CI 26.3–37.9) in Karonga and 34.9% (95% CI 27.2–43.4) in Lilongwe. Among those vaccinated, 28.7% had received one dose of the AstraZeneca-Oxford vaccine AZD1222 Vaxzeria (AZ) vaccine, 50% had received two doses of the AZ vaccine, and 21.3% had received one dose of the Janssen-Cilag International NV Ad26.COV2-S vaccine (J&J) vaccine, all derived from the ancestral B.1 strain. Self-reported praziquantel treatment for schistosomiasis was more frequently reported in Karonga, whereas reported symptoms potentially related to helminth infection (blood in stool or urine, and pain on urination) were comparable between sites (Supplementary Table 3). Helminth infection prevalence and species distribution Overall helminth prevalence (PCR-positive for ≥ 1 species) was higher in Karonga (19.0%, 95% CI 7.7–30.3) compared with Lilongwe (9.3%, 95% CI 0.0–25.7) (p = 0.021, 𝜒 2 test) (Fig. 1 a). The most frequently detected species were the hookworm N. americanus (hookworm) and Schistosoma spp. (Fig. 1 b). Neither A. lumbricoides nor T. trichiura were detected. Six individuals had multiple helminth infections: two were PCR-positive for Schistosoma spp. in both stool and urine, three were positive for N. americanus and Schistosoma spp. in stool, and one was positive for both common species of hookworm N. americanus and A. duodenale . Helminth prevalence did not differ by age, sex, or reported water contact (Supplementary Table 4, Supplementary Figs. 2,3). SARS-CoV-2 nAb prevalence by site and helminth status SARS-CoV-2 nAbs were detected more frequently in Lilongwe (65.9%, 95% CI 55.8–76.0) than in Karonga (50.8%, 95% CI 42.0–59.6) (Fig. 1 a). Participants without helminth infection had a higher nAb prevalence (59.1%, 95% CI 52.0–66.2) compared with helminth-infected participants (39.7%, 95% CI 19.7–59.7; p = 0.0094, 𝜒 2 test) (Fig. 1 c). Helminth infection impairs SARS-CoV-2 nAb response nAb titres were significantly higher in helminth-uninfected individuals (median = 314, IQR = 119–907) than in those infected with helminths (median = 129, IQR = 60.7–405, p < 0.0001, Wilcoxon rank-sum test). Although the difference was statistically significant, the effect size was small (Cliff’s δ = 0.295). A bootstrap simulation indicated 99.8% to detect this difference. Vaccinated individuals exhibited greater helminth-associated reduction in SARS-CoV-2 nAbs Participants were grouped by SARS-CoV-2 exposure history and variant: for those with natural infection (n = 109), nAb titres did not differ by helminth status for any variant assessed (p > 0.05 – Wilcoxon rank-sum tests) (Fig. 2 a). For COVID-19 vaccinated individuals (n = 18), those without helminth infection had substantially higher titres across all variants (Fig. 2 b). For the ancestral B.1 strain, the median neutralising antibody (nAb) titre among uninfected participants was 1177.2 (IQR 498.0–3887.1), compared with 132.8 (IQR 130.9–178.7) in helminth-infected individuals, a statistically significant difference (p = 0.012, Wilcoxon rank-sum test). Similar patterns were observed for other variants: Beta (739.8, IQR 255.4–1718.1 vs 88.4, IQR 74.5–149.8; p = 0.029), Delta (365.5, IQR 126.7–3169.7 vs 50, IQR 50–50; p = 0.023), Omicron BA.1 (278.4, IQR 81.6–451.7 vs 50, IQR 50–52.6; p = 0.033), and Omicron BA.2 (206.5, IQR 92.6–476.9 vs 50, IQR 50–56.1; p = 0.033), all assessed using Wilcoxon rank-sum tests. Among individuals with hybrid immunity (n = 76), helminth-uninfected participants had significantly higher neutralising antibody titres than helminth-infected individuals across multiple variants (Beta: 447.0, IQR 267.8–1078.8 vs 154.2, IQR 139.1–278.2, p = 0.020; Omicron BA.1: 304.5, IQR 136.2–877.8 vs 50, IQR 50–119.8, p = 0.0065; Omicron BA.2: 261.2, IQR 109.2–662.6 vs 84.0, IQR 63.8–100.9, p = 0.019) (Wilcoxon rank-sum tests; Fig. 2 c). Helminth species and infection intensity effects Contrary to our initial hypothesis that Schistosoma spp. was the primary driver of immunomodulation, SARS-CoV-2 nAb titres did not differ between participants infected with STHs ( A. duodenale and N. americanus ; n = 13) and those infected with Schistosoma spp. (n = 9) (p > 0.6 for all variants - Wilcoxon rank-sum test; Supplementary Fig. 4), though sample sizes were small. Helminth infection intensity, measured by qPCR Ct values were not found to correlate with SARS-CoV-2 nAb titres (Spearman’s R between − 0.34 and − 0.1; p > 0.05 for all SARS-CoV-2 variants) (Supplementary Fig. 5). Multivariable analysis of SARS-CoV-2 nAb determinants In the multivariate GAM model including all individuals with detectable nAbs (n = 203), age and the interaction between helminth status and COVID-19 vaccination were significant predictors. Vaccinated, helminth-infected individuals had 41% (95% CI 22–55%, p = 0.00017, Wald test) lower nAb titres than vaccinated, helminth-uninfected individuals (Supplementary Table 5). There was a significant linear relationship between age and nAb titres among these individuals with SARS-CoV-2 responses (n = 203) (estimated degrees of freedom (EDF) = 1, χ²=30.3, p < 0.0001, F-test) indicating that as age increased, nAb levels also increased (Supplementary Table 6) (Supplementary Fig. 6). A GAM model restricted to vaccinated participants (n = 94) identified helminth status and time since vaccination as significant predictors. Helminth-infected individuals had 29% lower titres (95% CI:16–41%, p = 0.0018, Wald test) (Supplementary Table 7). There was also a significant non-linear relationship between time since vaccination and nAb titres among vaccinated individuals (n = 94) (EDF = 6.72, χ²=46.8, p < 0.0001, F-test) (Supplementary Table 8). Neutralisation titres rose until ~ 100 days post-vaccination, remained stable until ~ 300 days, then began to decline (Supplementary Fig. 7). SARS-CoV-2 IgG responses by helminth infection status Among all SARS-CoV-2 exposed individuals (n = 238), helminth-infected individuals (n = 34) had lower S IgG levels (median 8.87, IQR 7.40–12.8) than helminth-uninfected individuals (n = 204) (median 12.3, IQR 9.13–15.4; p = 0.013 – Wilcoxon rank-sum test). However, when stratified by SARS-CoV-2 exposure history, differences in IgG responses by helminth status were not statistically significant (p > 0.05 for all comparisons – Wilcoxon rank-sum test) (Supplementary Fig. 8). For those COVID-19 vaccinated, helminth-infected individuals had a median absorbance 7.88 (IQR 6.76 to 10.3), while those helminth-uninfected had a median absorbance of 13.9 (IQR 6.76 to 10.3) (p = 0.41 – Wilcoxon rank-sum test). Discussion In this cross-sectional study of adults from rural and urban Malawi, helminth infection was associated with reduced SARS-CoV-2 nAb responses following COVID-19 vaccination, but not after natural infection. This pattern is consistent with existing literature demonstrating that chronic helminth infections can impair vaccine-induced immunity through immunoregulatory pathways, including IL-10 production and modified Th2 responses [ 16 , 17 ]. Helminth species distribution in our cohort was broadly comparable to national trends, although some differences were observed. N. americanus prevalence was lower in our study than in the Malawian DeWorm3 cohort [ 18 ], whereas A. duodenale was more common. T. trichiura and A. lumbricoides were rare, with no cases detected in this cohort. Notably, S. mansoni prevalence was higher than S. haematobium in our cohort, despite the latter being more prevalent nationally [ 19 ]. Although Schistosoma prevalence and symptom reporting were similar across sites, access to praziquantel treatment was lower in urban Lilongwe. This likely reflects historical prioritisation of mass drug administration programmes towards rural and lakeside populations considered high risk, potentially overlooking persistent transmission in urban and non–lake-residing populations [ 20 ]. Our findings differ from previous studies that reported no effect of helminth infections on SARS-CoV-2 nAb responses, however the studies assessed helminth species individually, specifically A. lumbricoides [ 5 ], O. viverrini [ 6 ] and O. volvulus [ 7 ], and T. spiralis [ 8 ] infections. We did not test for O. viverrine, O. volvulus , or T. spiralis in our study. Several factors may explain the discrepancies with the A. lumbricoides study. Firstly, the prevalence of A. lumbricoides among our participants was low, with Schistosoma spp. and N. americanus dominating the helminth infections. Second, the A. lumbricoides study only examined naturally infected participants [ 5 ], whereas our strongest effects were observed after vaccination. Third, differences in diagnostic approaches, serology vs. PCR, may influence classification of active vs. past infection. Finally, immune interactions may vary between helminth species and across epidemiological settings. Importantly, although we found no species-specific differences in neutralisation between STH and Schistosoma spp. , the small sample size limited our ability to draw firm conclusions. We initially hypothesised that the decreased nAb titres to SARS-CoV-2 were driven by the immunomodulatory properties of schistosome-derived molecules, such as omega-1 [ 21 ] and IPSE/alpha-1 [ 22 ]. However, multiple helminth species are known to induce overlapping regulatory pathways [ 23 ]; therefore, shared immunomodulatory effects, rather than species-specific mechanism may underlie the observed impairment of vaccine induced immunity. Consistent with this, chronic helminth infections in humans are associated with a broader immune-regulatory or “modified Th2” phenotype, characterised increased IL-10 production and IgG4 responses rather than a purely IL-4–driven response [ 16 ], which could suppress SARS-CoV-2 nAb generation. Helminth infection intensity, estimated by Ct value, was not associated with SARS-CoV-2 nAb titre. This may reflect limitations of Ct values as a proxy for infection intensity, particularly given species-specific variations in egg shedding, life cycle dynamics, and sampling variability. The absence of a detectable relationship could also reflect limited statistical power or heterogeneity in host immune responses. Our multivariable analyses identified the interaction between helminth infection and COVID-19 vaccination, but not natural infection, as a key determinant of neutralisation. This supports evidence from animal and human studies showing attenuated vaccine responses in the presence of helminth infection [ 1 , 17 , 24 ]. All participants received adenoviral-vector vaccines, which typically elicit lower neutralisation antibody levels than mRNA vaccines [ 25 ]. It is possible that helminth-related suppression may be less pronounced with mRNA platforms. Vaccination coverage in our cohort was modest (31.8% in Karonga; 34.9% in Lilongwe), consistent with national challenges during the study period, including limited vaccine supply and hesitancy. Such coverage may have limited population-level herd immunity, increasing reliance on infection-derived immunity and contributing to the observed neutralisation patterns. Spike IgG responses mirrored the neutralisation results, with overall lower SARS-CoV-2 IgG levels among helminth-infected individuals, although differences were not significant when stratified by exposure. Small sample size likely contributed, but trends suggest that helminth infection modulates SARS-CoV-2 immunity in a context-dependent manner, with the clearest effects following vaccination. Strengths of this study include the use of functional neutralisation assays across multiple variants, inclusion of both rural and urban populations, and adjustment for key confounders, such as age and time since COVID-19 vaccination. Limitations include the cross-sectional design, which precludes assessment of dynamic immune responses; exclusion of children and people living with HIV; lack of nutritional data, such as BMI; and insufficient power to compare vaccine platforms or dose. PCR detection captured active helminth infections, but not cumulative exposure, which may be immunologically relevant. Additionally, PCR Ct values were used as a proxy for helminth infection intensity rather than egg counts. Lastly, the study had limited power to assess species-specific effects and did not include data on immune mediators, such as cytokines or chemokines, limiting mechanistic insight. Overall, our findings suggest that helminth infection may impair COVID-19 vaccine responses in helminth-endemic regions. This has implications not only for COVID-19, but potentially for other vaccines deployed in similar settings [ 26 , 27 ]. Larger, longitudinal studies are needed to determine whether pre-vaccination deworming would improve vaccine immunogenicity, as prior work shows deworming can partially reverse immune inhibition [ 1 ] and enhance oral cholera vaccine effectiveness [ 28 ]. Evaluating alternative vaccine platforms, including mRNA vaccines, may also be informative. In summary, helminth infection was associated with reduced SARS-CoV-2 neutralisation following COVID-19 vaccination. Future work should assess the potential benefits of integrating pre-vaccination deworming with vaccination programmes and identify vaccine strategies that provide optimal protection in helminth-infected populations. Declarations Acknowledgements We thank the study participants, as well as the Malawi Epidemiology and Intervention Unit (MEIRU) field and laboratory teams. This work was supported by the Wellcome trust (grant numbers 217073/Z/19/Z to MC, 221989/Z/20/Z to MC and AH – held by the Malawi Epidemiology and Intervention Unit as part of the University of Glasgow) and the Medical Research Council (grant number MC_UU_00034/6 to AH). Author contributions Conceptualisation: MJM, ASA, AH, BJW Formal analysis: MJM Investigation: MJM, ECH, LB, SK, ASA, LS, HM Malawi study operations: ASA, SK, LB, AC Resources: AC, BJW Data curation: ASA, AH Writing - original draft: MJM, ASA, AH, BJW Writing - review & editing: All authors Visualisation: MJM Supervision: AC, ASA, AH, BJW Project administration: SK, ASA Funding acquisition: AC, ASA, AH, BJW Competing interests statement The authors declare no conflicts of interest. Data availability statement Requests for individual, pseudo-anonymised data and supporting documents can be sent to [email protected] , referencing the paper title. A data transfer agreement will be required. Ethics declarations Ethical approval was obtained from the Malawi College of Medicine Research Ethics Committee (P11/20/3177, 11 th December 2020), and the University of Glasgow (200200056, 8 th February 2021). 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McCormack","email":"data:image/png;base64,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","orcid":"","institution":"MRC University of Glasgow Centre for Virus Research","correspondingAuthor":true,"prefix":"","firstName":"Mhairi","middleName":"J.","lastName":"McCormack","suffix":""},{"id":627242803,"identity":"850b6344-18a7-4fa0-b426-2189e7128cea","order_by":1,"name":"Louis Banda","email":"","orcid":"","institution":"Malawi Epidemiology and Intervention Research Unit","correspondingAuthor":false,"prefix":"","firstName":"Louis","middleName":"","lastName":"Banda","suffix":""},{"id":627242804,"identity":"6907a190-73f9-4b3e-ba1f-83ab483c3e56","order_by":2,"name":"Stephen Kasenda","email":"","orcid":"","institution":"Malawi Epidemiology and Intervention Research Unit","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Kasenda","suffix":""},{"id":627242805,"identity":"abb46463-5f47-4580-abbf-837d6ede28e3","order_by":3,"name":"Lyson Samikwa","email":"","orcid":"","institution":"Kamuzu University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Lyson","middleName":"","lastName":"Samikwa","suffix":""},{"id":627242806,"identity":"682250d7-7fde-49e3-9cd3-31ebe272fe2a","order_by":4,"name":"Harry Meleke","email":"","orcid":"","institution":"Kamuzu University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Harry","middleName":"","lastName":"Meleke","suffix":""},{"id":627242807,"identity":"a94acfd5-b192-4668-a394-9e2c52a7318c","order_by":5,"name":"Ellen C. Hughes","email":"","orcid":"","institution":"MRC University of Glasgow Centre for Virus Research","correspondingAuthor":false,"prefix":"","firstName":"Ellen","middleName":"C.","lastName":"Hughes","suffix":""},{"id":627242808,"identity":"ee24ca52-4845-43ae-8ad3-20588641f641","order_by":6,"name":"Amelia Crampin","email":"","orcid":"","institution":"Malawi Epidemiology and Intervention Research Unit","correspondingAuthor":false,"prefix":"","firstName":"Amelia","middleName":"","lastName":"Crampin","suffix":""},{"id":627242809,"identity":"f23ff5ff-be87-43af-a960-42f1a2defdb9","order_by":7,"name":"David Chaima","email":"","orcid":"","institution":"Kamuzu University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Chaima","suffix":""},{"id":627242810,"identity":"62300520-9e90-4d86-92b9-9ca26370e8f9","order_by":8,"name":"Tonney Nyirenda","email":"","orcid":"","institution":"Kamuzu University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Tonney","middleName":"","lastName":"Nyirenda","suffix":""},{"id":627242811,"identity":"693818e6-c19f-4df2-b946-8ffba700dc94","order_by":9,"name":"Brian J. Willett","email":"","orcid":"","institution":"MRC University of Glasgow Centre for Virus Research","correspondingAuthor":false,"prefix":"","firstName":"Brian","middleName":"J.","lastName":"Willett","suffix":""},{"id":627242812,"identity":"2387a699-c0fb-4f51-83d2-c31166d98f5a","order_by":10,"name":"Abena S. Amoah","email":"","orcid":"","institution":"Leiden University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Abena","middleName":"S.","lastName":"Amoah","suffix":""},{"id":627242813,"identity":"91c4caaf-a37f-4fbe-b69b-58d4335d60e6","order_by":11,"name":"Antonia Ho","email":"","orcid":"","institution":"MRC University of Glasgow Centre for Virus Research","correspondingAuthor":false,"prefix":"","firstName":"Antonia","middleName":"","lastName":"Ho","suffix":""}],"badges":[],"createdAt":"2026-04-02 15:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9305049/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9305049/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107948636,"identity":"b169f98c-47bd-4993-97e0-db7d5b38010b","added_by":"auto","created_at":"2026-04-28 00:22:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73613,"visible":true,"origin":"","legend":"\u003cp\u003ePrevalence of helminth infections and SARS-CoV-2 neutralising antibodies (nAbs) in the cohort. (A) Prevalence by site (Karonga–rural; Lilongwe–urban) of helminth infections (dark blue) and SARS-CoV-2 nAbs (light blue). (B) Prevalence of each type of helminth type per site (Karonga–orange; Lilongwe–green) (C) SARS-CoV-2 nAb prevalence by helminth status (infected–dark pink; uninfected–light pink). Bars show percentages with 95% CI error bars.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9305049/v1/f2323921aa5f2f7fd11ad519.png"},{"id":107948637,"identity":"165b43fa-c2a7-4b96-b8c3-e0f06c258de2","added_by":"auto","created_at":"2026-04-28 00:22:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":419711,"visible":true,"origin":"","legend":"\u003cp\u003eSARS-CoV-2 neutralising antibody titres by helminth status across SARS-CoV-2 exposure histories. (A) SARS-CoV-2 infected only (n=109) - n=96 helminth-uninfected; n=13 helminth-infected (B) COVID-19 vaccinated only (n=18) - n=15 helminth-uninfected; n=3 helminth-infected (C) vaccinated and infected (hybrid immunity; n=76) - n=69 helminth-uninfected; n=7 helminth-infected. Antibody titres against each of the SARS-CoV-2 variants were measured using an HIV(SARS-CoV-2) pseudotyped virus neutralisation assay. Boxplots show median and IQR of 50% titres. The whiskers stretch to the farthest data points that lie within 1.5 × IQR of Q1 and Q3, while any points beyond this range are displayed as outliers. Wilcoxon (rank-sum) test with false discovery rate correction was used; p-values shown. Due to very small subgroup sizes, statistical comparisons should be interpreted with caution and are presented as exploratory analyses.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9305049/v1/04bcabf78670093046782488.png"},{"id":108007605,"identity":"04057127-87b2-4ac1-b265-32bf79460296","added_by":"auto","created_at":"2026-04-28 13:00:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":109458,"visible":true,"origin":"","legend":"\u003cp\u003eAnti-SARS-CoV-2 Spike IgG (Absorbance) by helminth status among those Spike (S) ELISA positive. Anti-SARS-CoV-2 S IgG measured with an enzyme linked immunosorbent assay (ELISA) using the ancestral B.1 S protein. 204 participants were helminth uninfected, 34 were helminth infected. Boxplots show median and IQR of 50% titres. The whiskers stretch to the farthest data points that lie within 1.5 × IQR of Q1 and Q3, while any points beyond this range are displayed as outliers. Wilcoxon (rank-sum) test was used; p-values shown.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9305049/v1/902bc800f462f5e3572ca54e.png"},{"id":108181092,"identity":"19639969-723e-4e13-b733-94450d6f1568","added_by":"auto","created_at":"2026-04-30 08:57:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":817906,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9305049/v1/abb0549e-30d7-439e-9165-431604dfb8ce.pdf"},{"id":107948635,"identity":"0911667e-7c9c-4b42-a988-c9182173562b","added_by":"auto","created_at":"2026-04-28 00:22:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2182325,"visible":true,"origin":"","legend":"","description":"","filename":"MJMSupplementaryMaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9305049/v1/c78732d2c2a3049c35c72294.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Helminth infection is linked to an impaired neutralisation response to SARS-CoV-2 post vaccination","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic helminth infections are known to modulate host immune responses to vaccines and pathogens, including SARS-CoV-2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Helminth-induced immunoregulation may reduce COVID-19 severity by dampening hyperinflammatory responses [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], yet the same regulation may also weaken vaccine-induced immunity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This is particularly relevant in sub-Saharan Africa, where helminth infections are endemic and may partly contribute to the comparatively lower burden of severe COVID-19 in the region. Mbow et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] proposed that helminths promote IL-4\u0026ndash;driven expansion of virtual memory T cells and reduce proinflammatory monocytes, thereby dampening cytokine storms and lung inflammation. Understanding these interactions is important for optimising COVID-19 control measures and vaccination strategies in helminth-endemic regions.\u003c/p\u003e \u003cp\u003eHowever, evidence on helminth\u0026ndash;SARS-CoV-2 interactions remains limited. Two studies in Ethiopia reported reduced COVID-19 severity among helminth-infected individuals [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], though neither examined SARS-CoV-2 antibodies. Other studies found no effect of infections with \u003cem\u003eAscaris lumbricoides\u003c/em\u003e, \u003cem\u003eOpisthorchis viverrine, Onchocerca volvulus\u003c/em\u003e, or \u003cem\u003eTrichinella spiralis\u003c/em\u003e on SARS-CoV-2 neutralising antibody (nAb) levels [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], although methodologies varied. The \u003cem\u003eAscaris\u003c/em\u003e, \u003cem\u003eOnchocerca, and Trichinella\u003c/em\u003e studies used serology to infer helminth exposure rather than demonstrating active infection [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], while the Opisthorchis study measured active infection and reported reduced RBD-specific IgG levels in co-infected individuals [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. One study observed impaired anti-SARS-CoV-2 S1 IgG responses in individuals with moderate or severe \u003cem\u003eSchistosoma mansoni\u003c/em\u003e infection compared with those Kato-Katz negative [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], however they had very limited participants, and did not assess functional immunity. Additionally, a recent study in Ghana reported higher helminth seroprevalence among COVID-19 asymptomatic individuals and an associated shift toward Th2-type immune responses [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we investigated whether current helminth infections as determined by real time PCR were associated with altered SARS-CoV-2 nAb responses in adults from rural and urban Malawi. These data provide insights into SARS-CoV-2 immunity in helminth-endemic settings and have implications for vaccination programmes.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eStudy population\u003c/p\u003e \u003cp\u003eThe study was conducted in Karonga (rural) and Lilongwe (urban, Area 25) (Supplementary Fig.\u0026nbsp;1), where \u003cem\u003eSchistosoma\u003c/em\u003e spp. and soil-transmitted helminth (STH) are endemic [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We included 371 adults participating in a longitudinal SARS-CoV-2 serosurveillance cohort [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Samples were collected cross-sectionally between January and April 2022 with written, informed consent. Individuals with HIV were excluded due to known interference of antiretroviral therapy with the pseudotype neutralisation assay [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSample collection and laboratory procedures\u003c/p\u003e \u003cp\u003eQuestionnaires captured demographic and clinical data (Supplementary Methods). Blood, stool and urine samples were collected. Serum was stored at \u0026minus;\u0026thinsp;80\u0026deg;C before transfer to the MRC-University of Glasgow Centre for Virus Research for SARS-CoV-2 neutralisation assays. Stool and urine samples were analysed at Kamuzu University of Health Sciences for helminth infection.\u003c/p\u003e \u003cp\u003eNeutralisation against ancestral B.1, Beta, Delta, Omicron BA.1, and BA.2 variants (Supplementary Table\u0026nbsp;1), the predominant variants circulating in Malawi before sample collection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], was measured using an HIV pseudotype-based assay. Vaccinated participants were tested for anti-nucleocapsid (N) IgG by ELISA to identify prior infection (Supplementary Methods). All participants were tested for anti-spike (S) IgG by ELISA to measure the overall IgG responses (Supplementary Methods).\u003c/p\u003e \u003cp\u003eDNA extracted from stool and urine was tested by real-time PCR for \u003cem\u003eSchistosoma\u003c/em\u003e spp., \u003cem\u003eA. lumbricoides, Ancylostoma duodenale, Necator americanus\u003c/em\u003e, and \u003cem\u003eTrichuris trichiura\u003c/em\u003e. Urine samples were tested for S\u003cem\u003echistosoma\u003c/em\u003e spp. (Supplementary Methods, Supplementary Table\u0026nbsp;2). Cycle threshold (Ct) values were used as a proxy for helminth infection intensity, with a lower Ct indicating higher intensity.\u003c/p\u003e \u003cp\u003eStatistical analyses\u003c/p\u003e \u003cp\u003eFor prevalence percentages, 95% binomial confidence intervals (CI) were reported. A two-proportion chi-squared test (two-tailed) was used to compare prevalence between groups. For nAb titres, the median and interquartile range (IQR) were presented as the data were not normally distributed. The non-parametric two-tailed Wilcoxon rank-sum test was used to assess statistical differences in titres. A false discovery rate (Benjamini-Hochberg) correction was applied when making multiple individual comparisons to reduce false positivity, while maintaining statistical power for the small sample size. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant, with very small p-values represented as p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001. Further statistical analyses methods that involved descriptive analysis of participants and effect size estimate methods, are described in the Supplementary Methods. Generalised additive models (GAMs) were used to evaluate predictors of nAb titres, including age, helminth infection status, vaccination, and time since vaccination (Supplementary Methods).\u003c/p\u003e \u003cp\u003eEthics declaration statement\u003c/p\u003e \u003cp\u003eEthical approval was obtained from the Malawi College of Medicine Research Ethics Committee (P11/20/3177, 11th December 2020), and the University of Glasgow (200200056, 8th February 2021).\u003c/p\u003e "},{"header":"Results","content":"\u003cp\u003eParticipant characteristics\u003c/p\u003e \u003cp\u003eOf 371 participants, 242 were from Karonga (rural) and 129 were from Lilongwe (urban). Median age was similar between sites (Karonga: 36.1 years, IQR 16.0\u0026ndash;50.0 years; Lilongwe: 38.2 years, IQR 28.3\u0026ndash;49.2 years; p\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;0.49, Wilcoxon test) (Supplementary Table\u0026nbsp;3). A lower proportion of participants in Karonga were female (p\u0026thinsp;=\u0026thinsp;0.002, \u0026#120594;\u003csup\u003e2\u003c/sup\u003e test). COVID-19 vaccination coverage was 31.8% (95% CI 26.3\u0026ndash;37.9) in Karonga and 34.9% (95% CI 27.2\u0026ndash;43.4) in Lilongwe. Among those vaccinated, 28.7% had received one dose of the AstraZeneca-Oxford vaccine AZD1222 Vaxzeria (AZ) vaccine, 50% had received two doses of the AZ vaccine, and 21.3% had received one dose of the Janssen-Cilag International NV Ad26.COV2-S vaccine (J\u0026amp;J) vaccine, all derived from the ancestral B.1 strain. Self-reported praziquantel treatment for schistosomiasis was more frequently reported in Karonga, whereas reported symptoms potentially related to helminth infection (blood in stool or urine, and pain on urination) were comparable between sites (Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eHelminth infection prevalence and species distribution\u003c/p\u003e \u003cp\u003eOverall helminth prevalence (PCR-positive for \u0026ge;\u0026thinsp;1 species) was higher in Karonga (19.0%, 95% CI 7.7\u0026ndash;30.3) compared with Lilongwe (9.3%, 95% CI 0.0\u0026ndash;25.7) (p\u0026thinsp;=\u0026thinsp;0.021, \u0026#120594;\u003csup\u003e2\u003c/sup\u003e test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The most frequently detected species were the hookworm \u003cem\u003eN. americanus\u003c/em\u003e (hookworm) and \u003cem\u003eSchistosoma\u003c/em\u003e spp. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Neither \u003cem\u003eA. lumbricoides\u003c/em\u003e nor \u003cem\u003eT. trichiura\u003c/em\u003e were detected.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSix individuals had multiple helminth infections: two were PCR-positive for \u003cem\u003eSchistosoma\u003c/em\u003e spp. in both stool and urine, three were positive for \u003cem\u003eN. americanus\u003c/em\u003e and \u003cem\u003eSchistosoma\u003c/em\u003e spp. in stool, and one was positive for both common species of hookworm \u003cem\u003eN. americanus\u003c/em\u003e and \u003cem\u003eA. duodenale\u003c/em\u003e. Helminth prevalence did not differ by age, sex, or reported water contact (Supplementary Table\u0026nbsp;4, Supplementary Figs.\u0026nbsp;2,3).\u003c/p\u003e \u003cp\u003eSARS-CoV-2 nAb prevalence by site and helminth status\u003c/p\u003e \u003cp\u003eSARS-CoV-2 nAbs were detected more frequently in Lilongwe (65.9%, 95% CI 55.8\u0026ndash;76.0) than in Karonga (50.8%, 95% CI 42.0\u0026ndash;59.6) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Participants without helminth infection had a higher nAb prevalence (59.1%, 95% CI 52.0\u0026ndash;66.2) compared with helminth-infected participants (39.7%, 95% CI 19.7\u0026ndash;59.7; p\u0026thinsp;=\u0026thinsp;0.0094, \u0026#120594;\u003csup\u003e2\u003c/sup\u003e test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eHelminth infection impairs SARS-CoV-2 nAb response\u003c/p\u003e \u003cp\u003enAb titres were significantly higher in helminth-uninfected individuals (median\u0026thinsp;=\u0026thinsp;314, IQR\u0026thinsp;=\u0026thinsp;119\u0026ndash;907) than in those infected with helminths (median\u0026thinsp;=\u0026thinsp;129, IQR\u0026thinsp;=\u0026thinsp;60.7\u0026ndash;405, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Wilcoxon rank-sum test). Although the difference was statistically significant, the effect size was small (Cliff\u0026rsquo;s δ\u0026thinsp;=\u0026thinsp;0.295). A bootstrap simulation indicated 99.8% to detect this difference.\u003c/p\u003e \u003cp\u003eVaccinated individuals exhibited greater helminth-associated reduction in SARS-CoV-2 nAbs\u003c/p\u003e \u003cp\u003eParticipants were grouped by SARS-CoV-2 exposure history and variant: for those with natural infection (n\u0026thinsp;=\u0026thinsp;109), nAb titres did not differ by helminth status for any variant assessed (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 \u0026ndash; Wilcoxon rank-sum tests) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). For COVID-19 vaccinated individuals (n\u0026thinsp;=\u0026thinsp;18), those without helminth infection had substantially higher titres across all variants (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). For the ancestral B.1 strain, the median neutralising antibody (nAb) titre among uninfected participants was 1177.2 (IQR 498.0\u0026ndash;3887.1), compared with 132.8 (IQR 130.9\u0026ndash;178.7) in helminth-infected individuals, a statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.012, Wilcoxon rank-sum test). Similar patterns were observed for other variants: Beta (739.8, IQR 255.4\u0026ndash;1718.1 vs 88.4, IQR 74.5\u0026ndash;149.8; p\u0026thinsp;=\u0026thinsp;0.029), Delta (365.5, IQR 126.7\u0026ndash;3169.7 vs 50, IQR 50\u0026ndash;50; p\u0026thinsp;=\u0026thinsp;0.023), Omicron BA.1 (278.4, IQR 81.6\u0026ndash;451.7 vs 50, IQR 50\u0026ndash;52.6; p\u0026thinsp;=\u0026thinsp;0.033), and Omicron BA.2 (206.5, IQR 92.6\u0026ndash;476.9 vs 50, IQR 50\u0026ndash;56.1; p\u0026thinsp;=\u0026thinsp;0.033), all assessed using Wilcoxon rank-sum tests. Among individuals with hybrid immunity (n\u0026thinsp;=\u0026thinsp;76), helminth-uninfected participants had significantly higher neutralising antibody titres than helminth-infected individuals across multiple variants (Beta: 447.0, IQR 267.8\u0026ndash;1078.8 vs 154.2, IQR 139.1\u0026ndash;278.2, p\u0026thinsp;=\u0026thinsp;0.020; Omicron BA.1: 304.5, IQR 136.2\u0026ndash;877.8 vs 50, IQR 50\u0026ndash;119.8, p\u0026thinsp;=\u0026thinsp;0.0065; Omicron BA.2: 261.2, IQR 109.2\u0026ndash;662.6 vs 84.0, IQR 63.8\u0026ndash;100.9, p\u0026thinsp;=\u0026thinsp;0.019) (Wilcoxon rank-sum tests; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHelminth species and infection intensity effects\u003c/p\u003e \u003cp\u003eContrary to our initial hypothesis that \u003cem\u003eSchistosoma\u003c/em\u003e spp. was the primary driver of immunomodulation, SARS-CoV-2 nAb titres did not differ between participants infected with STHs (\u003cem\u003eA. duodenale\u003c/em\u003e and \u003cem\u003eN. americanus\u003c/em\u003e; n\u0026thinsp;=\u0026thinsp;13) and those infected with \u003cem\u003eSchistosoma\u003c/em\u003e spp. (n\u0026thinsp;=\u0026thinsp;9) (p\u0026thinsp;\u0026gt;\u0026thinsp;0.6 for all variants - Wilcoxon rank-sum test; Supplementary Fig.\u0026nbsp;4), though sample sizes were small.\u003c/p\u003e \u003cp\u003eHelminth infection intensity, measured by qPCR Ct values were not found to correlate with SARS-CoV-2 nAb titres (Spearman\u0026rsquo;s R between \u0026minus;\u0026thinsp;0.34 and \u0026minus;\u0026thinsp;0.1; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all SARS-CoV-2 variants) (Supplementary Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003eMultivariable analysis of SARS-CoV-2 nAb determinants\u003c/p\u003e \u003cp\u003eIn the multivariate GAM model including all individuals with detectable nAbs (n\u0026thinsp;=\u0026thinsp;203), age and the interaction between helminth status and COVID-19 vaccination were significant predictors. Vaccinated, helminth-infected individuals had 41% (95% CI 22\u0026ndash;55%, p\u0026thinsp;=\u0026thinsp;0.00017, Wald test) lower nAb titres than vaccinated, helminth-uninfected individuals (Supplementary Table\u0026nbsp;5). There was a significant linear relationship between age and nAb titres among these individuals with SARS-CoV-2 responses (n\u0026thinsp;=\u0026thinsp;203) (estimated degrees of freedom (EDF)\u0026thinsp;=\u0026thinsp;1, χ\u0026sup2;=30.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, F-test) indicating that as age increased, nAb levels also increased (Supplementary Table\u0026nbsp;6) (Supplementary Fig.\u0026nbsp;6).\u003c/p\u003e \u003cp\u003eA GAM model restricted to vaccinated participants (n\u0026thinsp;=\u0026thinsp;94) identified helminth status and time since vaccination as significant predictors. Helminth-infected individuals had 29% lower titres (95% CI:16\u0026ndash;41%, p\u0026thinsp;=\u0026thinsp;0.0018, Wald test) (Supplementary Table\u0026nbsp;7). There was also a significant non-linear relationship between time since vaccination and nAb titres among vaccinated individuals (n\u0026thinsp;=\u0026thinsp;94) (EDF\u0026thinsp;=\u0026thinsp;6.72, χ\u0026sup2;=46.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, F-test) (Supplementary Table\u0026nbsp;8). Neutralisation titres rose until ~\u0026thinsp;100 days post-vaccination, remained stable until ~\u0026thinsp;300 days, then began to decline (Supplementary Fig.\u0026nbsp;7).\u003c/p\u003e \u003cp\u003eSARS-CoV-2 IgG responses by helminth infection status\u003c/p\u003e \u003cp\u003eAmong all SARS-CoV-2 exposed individuals (n\u0026thinsp;=\u0026thinsp;238), helminth-infected individuals (n\u0026thinsp;=\u0026thinsp;34) had lower S IgG levels (median 8.87, IQR 7.40\u0026ndash;12.8) than helminth-uninfected individuals (n\u0026thinsp;=\u0026thinsp;204) (median 12.3, IQR 9.13\u0026ndash;15.4; p\u0026thinsp;=\u0026thinsp;0.013 \u0026ndash; Wilcoxon rank-sum test). However, when stratified by SARS-CoV-2 exposure history, differences in IgG responses by helminth status were not statistically significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all comparisons \u0026ndash; Wilcoxon rank-sum test) (Supplementary Fig.\u0026nbsp;8). For those COVID-19 vaccinated, helminth-infected individuals had a median absorbance 7.88 (IQR 6.76 to 10.3), while those helminth-uninfected had a median absorbance of 13.9 (IQR 6.76 to 10.3) (p\u0026thinsp;=\u0026thinsp;0.41 \u0026ndash; Wilcoxon rank-sum test).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this cross-sectional study of adults from rural and urban Malawi, helminth infection was associated with reduced SARS-CoV-2 nAb responses following COVID-19 vaccination, but not after natural infection. This pattern is consistent with existing literature demonstrating that chronic helminth infections can impair vaccine-induced immunity through immunoregulatory pathways, including IL-10 production and modified Th2 responses [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHelminth species distribution in our cohort was broadly comparable to national trends, although some differences were observed. \u003cem\u003eN. americanus\u003c/em\u003e prevalence was lower in our study than in the Malawian DeWorm3 cohort [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], whereas \u003cem\u003eA. duodenale\u003c/em\u003e was more common. \u003cem\u003eT. trichiura\u003c/em\u003e and \u003cem\u003eA. lumbricoides\u003c/em\u003e were rare, with no cases detected in this cohort. Notably, \u003cem\u003eS. mansoni\u003c/em\u003e prevalence was higher than \u003cem\u003eS. haematobium\u003c/em\u003e in our cohort, despite the latter being more prevalent nationally [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Although \u003cem\u003eSchistosoma\u003c/em\u003e prevalence and symptom reporting were similar across sites, access to praziquantel treatment was lower in urban Lilongwe. This likely reflects historical prioritisation of mass drug administration programmes towards rural and lakeside populations considered high risk, potentially overlooking persistent transmission in urban and non\u0026ndash;lake-residing populations [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur findings differ from previous studies that reported no effect of helminth infections on SARS-CoV-2 nAb responses, however the studies assessed helminth species individually, specifically \u003cem\u003eA. lumbricoides\u003c/em\u003e [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], \u003cem\u003eO. viverrini\u003c/em\u003e [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and \u003cem\u003eO. volvulus\u003c/em\u003e [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and \u003cem\u003eT. spiralis\u003c/em\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] infections. We did not test for \u003cem\u003eO. viverrine, O. volvulus\u003c/em\u003e, or \u003cem\u003eT. spiralis\u003c/em\u003e in our study. Several factors may explain the discrepancies with the \u003cem\u003eA. lumbricoides\u003c/em\u003e study. Firstly, the prevalence of \u003cem\u003eA. lumbricoides\u003c/em\u003e among our participants was low, with \u003cem\u003eSchistosoma\u003c/em\u003e spp. and \u003cem\u003eN. americanus\u003c/em\u003e dominating the helminth infections. Second, the \u003cem\u003eA. lumbricoides\u003c/em\u003e study only examined naturally infected participants [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], whereas our strongest effects were observed after vaccination. Third, differences in diagnostic approaches, serology vs. PCR, may influence classification of active vs. past infection. Finally, immune interactions may vary between helminth species and across epidemiological settings. Importantly, although we found no species-specific differences in neutralisation between STH and \u003cem\u003eSchistosoma spp.\u003c/em\u003e, the small sample size limited our ability to draw firm conclusions. We initially hypothesised that the decreased nAb titres to SARS-CoV-2 were driven by the immunomodulatory properties of schistosome-derived molecules, such as omega-1 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and IPSE/alpha-1 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, multiple helminth species are known to induce overlapping regulatory pathways [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; therefore, shared immunomodulatory effects, rather than species-specific mechanism may underlie the observed impairment of vaccine induced immunity. Consistent with this, chronic helminth infections in humans are associated with a broader immune-regulatory or \u0026ldquo;modified Th2\u0026rdquo; phenotype, characterised increased IL-10 production and IgG4 responses rather than a purely IL-4\u0026ndash;driven response [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], which could suppress SARS-CoV-2 nAb generation.\u003c/p\u003e \u003cp\u003eHelminth infection intensity, estimated by Ct value, was not associated with SARS-CoV-2 nAb titre. This may reflect limitations of Ct values as a proxy for infection intensity, particularly given species-specific variations in egg shedding, life cycle dynamics, and sampling variability. The absence of a detectable relationship could also reflect limited statistical power or heterogeneity in host immune responses.\u003c/p\u003e \u003cp\u003eOur multivariable analyses identified the interaction between helminth infection and COVID-19 vaccination, but not natural infection, as a key determinant of neutralisation. This supports evidence from animal and human studies showing attenuated vaccine responses in the presence of helminth infection [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. All participants received adenoviral-vector vaccines, which typically elicit lower neutralisation antibody levels than mRNA vaccines [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It is possible that helminth-related suppression may be less pronounced with mRNA platforms. Vaccination coverage in our cohort was modest (31.8% in Karonga; 34.9% in Lilongwe), consistent with national challenges during the study period, including limited vaccine supply and hesitancy. Such coverage may have limited population-level herd immunity, increasing reliance on infection-derived immunity and contributing to the observed neutralisation patterns.\u003c/p\u003e \u003cp\u003eSpike IgG responses mirrored the neutralisation results, with overall lower SARS-CoV-2 IgG levels among helminth-infected individuals, although differences were not significant when stratified by exposure. Small sample size likely contributed, but trends suggest that helminth infection modulates SARS-CoV-2 immunity in a context-dependent manner, with the clearest effects following vaccination.\u003c/p\u003e \u003cp\u003eStrengths of this study include the use of functional neutralisation assays across multiple variants, inclusion of both rural and urban populations, and adjustment for key confounders, such as age and time since COVID-19 vaccination. Limitations include the cross-sectional design, which precludes assessment of dynamic immune responses; exclusion of children and people living with HIV; lack of nutritional data, such as BMI; and insufficient power to compare vaccine platforms or dose. PCR detection captured active helminth infections, but not cumulative exposure, which may be immunologically relevant. Additionally, PCR Ct values were used as a proxy for helminth infection intensity rather than egg counts. Lastly, the study had limited power to assess species-specific effects and did not include data on immune mediators, such as cytokines or chemokines, limiting mechanistic insight.\u003c/p\u003e \u003cp\u003eOverall, our findings suggest that helminth infection may impair COVID-19 vaccine responses in helminth-endemic regions. This has implications not only for COVID-19, but potentially for other vaccines deployed in similar settings [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Larger, longitudinal studies are needed to determine whether pre-vaccination deworming would improve vaccine immunogenicity, as prior work shows deworming can partially reverse immune inhibition [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and enhance oral cholera vaccine effectiveness [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Evaluating alternative vaccine platforms, including mRNA vaccines, may also be informative.\u003c/p\u003e \u003cp\u003eIn summary, helminth infection was associated with reduced SARS-CoV-2 neutralisation following COVID-19 vaccination. Future work should assess the potential benefits of integrating pre-vaccination deworming with vaccination programmes and identify vaccine strategies that provide optimal protection in helminth-infected populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the study participants, as well as the Malawi Epidemiology and Intervention Unit (MEIRU) field and laboratory teams. This work was supported by\u0026nbsp;the Wellcome trust (grant numbers 217073/Z/19/Z to MC, 221989/Z/20/Z to MC and AH \u0026ndash; held by the Malawi Epidemiology and Intervention Unit as part of the University of Glasgow) and the Medical Research Council (grant number MC_UU_00034/6 to AH).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualisation: MJM, ASA, AH, BJW\u003c/p\u003e\n\u003cp\u003eFormal analysis: MJM\u003c/p\u003e\n\u003cp\u003eInvestigation: MJM, ECH, LB, SK, ASA, LS, HM\u003c/p\u003e\n\u003cp\u003eMalawi study operations: ASA, SK, LB, AC\u003c/p\u003e\n\u003cp\u003eResources: AC, BJW\u003c/p\u003e\n\u003cp\u003eData curation: ASA, AH\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWriting - original draft: MJM, ASA, AH, BJW\u003c/p\u003e\n\u003cp\u003eWriting - review \u0026amp; editing: All authors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVisualisation: MJM\u003c/p\u003e\n\u003cp\u003eSupervision: AC, ASA, AH, BJW\u003c/p\u003e\n\u003cp\u003eProject administration: SK, ASA\u003c/p\u003e\n\u003cp\u003eFunding acquisition: AC, ASA, AH, BJW\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRequests for individual, pseudo-anonymised data and supporting documents can be sent to [email protected], referencing the paper title. A data transfer agreement will be required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the Malawi College of Medicine Research Ethics Committee (P11/20/3177, 11\u003csup\u003eth\u003c/sup\u003e December 2020), and the University of Glasgow (200200056, 8\u003csup\u003eth\u003c/sup\u003e February 2021). All experiments were performed in accordance with institutional and regional guidelines and regulations. 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Immun.\u003c/em\u003e \u003cb\u003e69\u003c/b\u003e, 1574\u0026ndash;1580. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1128/iai.69.3.1574-1580.2001\u003c/span\u003e\u003cspan address=\"10.1128/iai.69.3.1574-1580.2001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2001).\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"SARS-CoV-2, helminth, neutralisation, antibody, vaccination","lastPublishedDoi":"10.21203/rs.3.rs-9305049/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9305049/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChronic helminth infections can modulate immune responses to infection and vaccination. This study explored the association between current helminth infection, including waterborne and soil-transmitted helminths (STHs), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody (nAb) responses. Samples were collected cross-sectionally from participants across rural (Karonga) and urban (Lilongwe) regions in Malawi. Helminth infections were detected via real-time PCR in stool and urine samples, targeting \u003cem\u003eSchistosoma\u003c/em\u003e spp., \u003cem\u003eAscaris lumbricoides\u003c/em\u003e, \u003cem\u003eAncylostoma duodenale\u003c/em\u003e, \u003cem\u003eNecator americanus\u003c/em\u003e, and \u003cem\u003eTrichuris trichiura\u003c/em\u003e. SARS-CoV-2 nAbs were measured using a human immunodeficiency virus (HIV) pseudotyped virus neutralisation assay. A nucleocapsid (N) protein enzyme linked immunosorbent assay (ELISA) identified prior natural SARS-CoV-2 infection in vaccinated participants. IgG targeting the spike (S) protein was measured using an ELISA. Helminth infection was found to be associated with reduced nAb responses post coronavirus disease 2019 (COVID-19) vaccination, but not after natural SARS-CoV-2 infection. IgG responses were also impaired among those helminth-infected. Generalised additive model analysis confirmed this interaction while considering covariates. This suggests that deworming before vaccination may improve responses in helminth endemic regions.\u003c/p\u003e","manuscriptTitle":"Helminth infection is linked to an impaired neutralisation response to SARS-CoV-2 post vaccination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 00:22:43","doi":"10.21203/rs.3.rs-9305049/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-15T14:15:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T09:38:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158273563497967260818034641472875344731","date":"2026-04-28T09:17:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"305672709465121563154883845471204173738","date":"2026-04-27T16:12:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32388967041695460676171075550117036138","date":"2026-04-27T14:04:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-19T13:11:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-14T08:14:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-08T11:18:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-04-08T10:35:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bffe7e39-39c7-4bc1-bc38-960273f46948","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-15T14:15:53+00:00","index":50,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T09:38:50+00:00","index":49,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66761018,"name":"Health sciences/Diseases"},{"id":66761019,"name":"Biological sciences/Immunology"},{"id":66761020,"name":"Health sciences/Medical research"},{"id":66761021,"name":"Biological sciences/Microbiology"}],"tags":[],"updatedAt":"2026-04-28T00:22:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 00:22:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9305049","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9305049","identity":"rs-9305049","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}