COVID-19 vaccination survey and anti-SARS-CoV-2 S1 IgG responses in a human cohort from Schistosoma mansoni-endemic villages in Mayuge, Uganda: A cross-sectional study

doi:10.21203/rs.3.rs-4983466/v1

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COVID-19 vaccination survey and anti-SARS-CoV-2 S1 IgG responses in a human cohort from Schistosoma mansoni-endemic villages in Mayuge, Uganda: A cross-sectional study

https://doi.org/10.21203/rs.3.rs-4983466/v1

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Introduction: Coronavirus disease 2019 (COVID-19) pandemic precipitated devastating health and economic consequences globally. Vaccination has been a central pillar for COVID-19 prevention and control. Understanding the immunomodulatory effects of helminth infections on COVID-19 vaccine-induced immune responses and vaccine efficacy is crucial to the development and deployment of effective vaccination strategies in low- and middle-income countries with high prevalence of worms.

Methods: In September 2022, we conducted a cross-sectional, population-based survey in five Schistosoma mansoniendemic villages in Mayuge District, Uganda (n=450). The prevalence of schistosomiasis and soil-transmitted helminths was determined by the Kato-Katz (KK) technique on two stool samples collected from each participant. A subset of individuals (n=204) were interviewed in a COVID-19 vaccination survey. IgG levels against the SARS-CoV-2 spike S1 subunit (Anti-S1 IgG) were measured by enzyme-linked immunosorbent assay (ELISA) assays using collected serum samples.

Results: The overall schistosomiasis and hookworm prevalence in the five villages was 36.4% (166/450) and 36.9% (168/450), respectively. Within the cohort, 69.78% (314/450) subjects showed a positive anti-S1 IgG response. COVID-19 vaccination coverage in interviewed participants was 93.14% (190/204; 95% CI, 88.8% − 95.9%). However, 81% (154/190) COVID-19 vaccinees had an anti-S1 IgG titer ≤ 200. In an adolescent group receiving a single dose of BNT162b2 vaccine (n=23), an inverse correlation was observed between anti-S1 IgG antibody levels/titers and faecal egg counts. Within the above group, anti-S1 IgG levels/titers were significantly low in subjects with a moderate-to-heavy S. mansoni infections (n=5) compared with KK-negative individuals (n=9). IgG1 was the dominant IgG subclass in sub-groups vaccinated with a single dose of the BNT162b2 (n=23) or Ad26.COV2.S (n=18).

Conclusion: Although the acceptance rate of COVID-19 vaccination was high, the majority of participants received only a single vaccine dose and the overall anti-S1 IgG titers in confirmed vaccinees were low. Moderate-to-heavy intensity schistosome infections blunted the antibody response following vaccination with a single dose of BNT162b2. These observations confirm the necessity for a second vaccine dose for two-dose primary immunization series and call for implementation research that may inform the development of a ‘treat and vaccinate’ policy during vaccination roll-out in regions with heavy worm burdens.

COVID-19

SARS-CoV-2

coronavirus

Schistosomiasis

Schistosoma mansoni

helminth

vaccine

Uganda

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 700 million people and caused more than 7.3 million reported deaths worldwide [1]. Uganda experienced two major waves of COVID-19 in late 2020 and late April 2021. As of 23 October 2022, a total of 169,473 confirmed cases and 3,630 deaths had been reported [2], resulting in an infection rate of approximately 0.3%. It has been suggested that a possible reason for this lower mortality in the country may be the presence of pre-existing cross-reactive immunological responses [3]. While a previous infection with a common human coronavirus (hCoV) may enhance the immune response to SARS-CoV-2 infection, such ‘cross-reactive immunity’ declines with age [4, 5]. Previous hCoV exposure may also cause serological cross-reactivity with SARS-CoV-2 antigens, particularly the nucleoprotein [6, 7]. A COVID-19 vaccination campaign was launched in Uganda on 10 March 2021 [8]. A number of COVID-19 vaccines including ChAdOx1 (AstraZeneca), Ad26.COV2.S (Johnson and Johnson/Janssen), CoronaVac (Sinovac), BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), have been administrated in the country. Most of these, such as ChAdOx1, Ad26.COV2.S, BNT162b2 and mRNA-1273, elicit strong Th1-biased responses [9–11]. By 26 November 2023, 44% of the total population in Uganda was vaccinated with at least one dose of a COVID-19 vaccine, while 29% of the population was vaccinated with a complete primary series of a COVID-19 vaccine [1].

Helminths are extremely common and highly prevalent infections of humans in Low- and Middle-income Countries (LMICs) where coinfection with helminths and SARS-CoV-2 may occur. Coinfections may increase in these countries because basic medical services and government resources needed for anti-helminth public health campaigns have been diverted for COVID-19 during the pandemic. Chronic infections with soil-transmitted helminths (STHs), schistosomes and filarial worms in LMICs alter the immune system towards a type 2 (Th2) immunity [12] together with Treg-mediated immune responses [13]. Some evidence suggests that prior helminth infection may impair host immune responses to vaccines against other types of pathogens [14–19]. However, other studies have found that helminth infection has limited influence on the immunogenicity of vaccines [20, 21]. There has been a call to action for the scientific research community and funding agencies to support clinical trials of COVID-19 vaccines in people with helminth infections as a priority population that represents a quarter of humanity [22].

Uganda has a high prevalence of schistosomiasis and other helminthiasis [23], which may affect immune responses in endemic communities following COVID-19 vaccination. However, no previous studies of COVID-19 vaccination coverage and vaccine-induced antibody responses have been reported in rural schistosomiasis-endemic areas of Uganda. In this study, we recruited 450 subjects from five schistosomiasis-endemic villages in Mayuge District, to conduct a survey on the prevalence of schistosomiasis and soil-transmitted helminthiasis and COVID-19 vaccine coverage. As the SARS-CoV-2 spike protein, particularly the S1 subunit (S1), is the primary target for eliciting of neutralising antibody responses [24], we measured IgG antibodies against the S1 subunit using serum samples collected from participants. Overall, the three primary objectives of the study were 1) to assess the COVID-19 vaccination status in the rural schistosomiasis endemic areas; 2) to estimate the approximate distribution of antibody levels/titers against the S1 protein in COVID-19 vaccinees; 3) to investigate the effects of schistosome infection intensity on serological responses against the S1 subunit in COVID-19 vaccinees.

2.1 Ethics

Ethical approval

for the study was obtained from the Institutional Review Board, Vector Control Division, Ministry of Health, Uganda (IRB number VCDREC160) and the Human Ethics Committee of QIMR Berghofer Medical Research Institute (QIMRB) (project number: P3700). All participants gave written informed consent (for individuals aged 18 or under, consent was obtained from their legal guardians prior to the administration of survey and sampling). The research protocol was approved by the Uganda National Council for Science and Technology (UNCST) (ref: UNCST/INV/870).

2.2 Study design and period

A representative descriptive and analytical cross-sectional study was conducted from 16 to 28 September 2022. By October 2022, two COVID-19 epidemic waves had occurred in Uganda, with a total of 169,473 confirmed cases and 3,630 deaths [2].

2.3 Setting

Uganda is an East African country with a total area of 241,038 km² and an estimated population of 49.6 million in 2023. The country’s gross domestic product per capita is 3,340 international dollars in 2024 [25]. Its human development index stands at 0.55 as of 2022, positioning it at 159 out of 193 countries and territories [26].

2.4 Study population

The target population was the residents of five villages in Mayuge District, including Bugoto, Bwondha, Musubi, Bukizibu, and Igeyero (Fig. 1). Inclusion criteria included: a) being over 5 years of age; b) giving informed consent or assent to participate in the study and to provide two stool samples and one blood sample. A total of 450 participants were enrolled.

2.5 Data and sample collection

Data collection was carried out by qualified research staff trained in survey procedures. Data were collected from consenting participants during interviews using a structured questionnaire to elicit information on socio-demographic characteristics, deworming history, attitudes and practices related to schistosomiasis. Information on COVID-19 vaccination status was also collected from a subset of participants (n = 204).

Two stool samples were collected from each individual on two separate days, for Kato-Katz (KK) detection (3 slides per stool sample) of eggs of S. mansoni, hookworm, Trichuris trichiura, Ascaris lumbricoides and other helminths.

A 10 ml peripheral venous blood sample was collected from each participant in blue-top sodium citrate tubes and allowed to clot for 30 minutes at room temperature. Whole blood samples were stored in a container at 4°C and then transferred to the laboratory, where serum samples were obtained after centrifugation at 1500 × g for 10 min. The samples were then aliquoted (~ 1.5 ml per aliquot) into three cryovials and stored at -20°C before being shipped on dry ice to QIMRB for further analysis. A Material Transfer Agreement (MTA) was completed prior to sample transfer.

2.6 Serological analyses

Serum samples were kept frozen at -80°C until analysis. An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels/titers of serum IgG antibody to the SARS-CoV-2 spike S1 protein (anti-S1 IgG), as previously described with minor modification [27, 28]. Briefly, recombinant SARS-CoV-2 S1 protein (aa14-683, accession number: YP_009724390.1) (Cat# RP87681; Thermo Fisher Scientific, Australia) was coated on 96-well MaxiSorp plates at a concentration of 1 ng/µL (100 µL/well) in coating buffer overnight at 4°C. The plates were washed once with PBST solution (phosphate-buffered saline, pH 7.5, containing 0.05% Tween-20) and incubated with blocking buffer (PBST containing 1% BSA) at 37°C for 1 hour. For anti-S1 IgG detection in the cohort, serum samples were diluted 1:100 in blocking buffer. For anti-S1 IgG titer determination, serial two-fold dilutions of sera were prepared from 1:100 to 1:3200. After adding 100 µL of diluted serum sample to each well, the plates were incubated at 37°C for 1 hour followed by the addition of a mouse monoclonal anti-human IgG (Fc specific)-biotin antibody (Cat# B3773, Merck Life Science, Australia) as secondary antibody (1:160,000, 100 µL/well) at 37°C for 1 hour. Plates were then incubated with streptavidin-HRP (Cat# 554066, BD Biosciences, CA, USA) (1:10,000, 100 µL/well) to detect antibodies bound to S protein. Plates were washed 5 times with wash buffer after each step following the addition of sera. TMB substrate (100 µL) (Cat# 860336; Merck Life Science, Australia) was then added to the plates and the reactions were terminated by adding 50 µL stop solution (2N H₂SO₄). Optical density (OD) was measured at 450 nm using a microplate spectrophotometer (PowerWave XS2, BioTek, VT, US). Pre-pandemic sera collected from Heilongjiang Province, China, before the outbreak of COVID-19 served as negative controls (n = 20) [29, 30]. The cut-off value for a positive reaction was calculated as 2.1 multiplied by the mean of OD₄₅₀ values of negative controls.

To assess the serum distribution of anti-S1 IgG subclasses, the MaxiSorp plates were coated with the S1 recombinant protein (100 ng/well). The plates were incubated overnight at 4°C and blocked with blocking buffer for 1 hour at 37°C. Serum samples were tested at 1:100. The following mouse anti-human IgG secondary antibodies were used: IgG1 1:500 (Cat# A-10648; Thermo Fisher Scientific, Australia), IgG2 1:500 (Cat# 05-0520; Thermo Fisher Scientific, Australia), IgG3 1:500 (Cat# 05-3620; Thermo Fisher Scientific, Australia), and IgG4 1:500 (Cat# A-10654; Thermo Fisher Scientific, Australia).

2.7 Statistical analysis

Statistical data were analysed using GraphPad Prism (v.9) for Windows (GraphPad Software, Inc., San Diego, CA, USA). IgG titers were natural log transformed. Mann-Whitney U test, Kruskal-Wallis test followed by Dunn’s multiple comparison test or one-way ANOVA test followed by Turkey’s comparison were used to detect differences between groups. Correlations between IgG OD values and titers in the ELISA assays and faecal egg counts [expressed in eggs per gram (EPG)] from the KK test results were determined by Spearman’s correlation coefficient after natural log transformation ln(Y + 1), where ‘Y’ represents EPG. Comparisons of data with a p value < 0.05 were considered statistically significant.

3.1 Demographic and clinical characteristics

A total of 450 participants were included in the current study, with 100 each from Bugoto, Bwondha, Musubi, and Bukizibu, and 50 from Igeyero (Table 1). Of these subjects included 198 males and 252 females. The median age of the participants was 14 years old, ranging from 5 to 78 years, with the age group 10-19 years predominating in the study population (n = 266, 59.1%). About one third of the individuals were infected with S. mansoni (36.4%) or hookworm (36.9%) as confirmed by the KK method. Among participants with schistosome infection, the median EPG of faecal egg burden was 31.7 (range 4 - 3246), with 67.5, 20.5 and 10.8% of participants having a light-, moderate- and heavy-infection, respectively (Supplementary Table S1). Of the subjects with hookworm, the majority (n = 166, 98.8%) had a light infection (EPG: 1-1,999) (Supplementary Table S1). Seventy-two subjects were co-infected with S. mansoni and hookworm. In addition, 0.2, 1.3, and 7.3% of subjects were infected with Ascaris, Trichuris or other helminths, respectively (Table 1).

Table 1. Sociodemographic characteristics and helminth infection of study participants in five schistosomiasis endemic villages in Mayuge District, Uganda.

Characteristics	Bugoto	Bwondha	Musubi	Bukizibu	Igeyero	Total
	N =100	N =100	N =100	N =100	N =50	N =450
Age groups (years)
<10	20 (20.0)	6 (6.0)	6 (6.0)	20 (20.0)	0 (0.0)	52 (11.6)
10-19	46 (46.0)	55 (55.0)	68 (68.0)	47 (47.0)	50 (100.0)	266 (59.1)
20-29	1 (1.0)	7 (7.0)	8 (8.0)	10 (10.0)	0 (0.0)	26 (5.8)
30-39	10 (10.0)	18 (18.0)	11 (11.0)	11 (11.0)	0 (0.0)	50 (11.1)
40-49	12 (12.0)	10 (10.0)	4 (4.0)	6 (6.0)	0 (0.0)	32 (7.1)
50-59	9 (9.0)	2 (2.0)	2 (2.0)	5 (5.0)	0 (0.0)	18 (4.0)
>60	2 (2.0)	2 (2.0)	1 (1.0)	1 (1.0)	0 (0.0)	6 (1.3)
Sex
Male	43 (43.0)	42 (42.0)	47 (47.0)	42 (42.0)	24 (48.0)	198 (44.0)
Female	57 (57.0)	58 (58.0)	53 (53.0)	58 (58.0)	26 (52.0)	252 (56.0)
*Schistosoma mansoni*
Yes	49 (49.0)	49 (49.0)	40 (40.0)	23 (23.0)	3 (6.0)	164 (36.4)
No	51 (51.0)	51 (51.0)	60 (60.0)	77 (77.0)	47 (94.0)	286 (63.6)
Hookworm
Yes	28 (28.0)	38 (38.0)	38 (38.0)	51 (51.0)	13 (26.0)	168 (36.9)
No	72 (72.0)	62 (62.0)	62 (62.0)	49 (49.0)	37 (74.0)	284 (63.1)
*Ascaris*
Yes	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.0)	0 (0.0)	1 (0.2)
No	100 (100.0)	100 (100.0)	100 (100.0)	99 (99.0)	50 (100.0)	449 (99.8)
*Trichuris*
Yes	0 (0.0)	6 (6.0)	0 (0.0)	0 (0.0)	0 (0.0)	6 (1.3)
No	100 (100.0)	94 (94.0)	100 (100.0)	100 (100.0)	50 (100.0)	444 (98.7)
*Others (Taenia, Heterophydes,* E. vermicularis, Hymenolepis nana)
Yes	6 (6.0)	6 (6.0)	6 (6.0)	10 (10.0)	5 (10.0)	33 (7.3)
No	94 (94.0)	94 (94.0)	94 (94.0)	90 (90.0)	45 (90.0)	417 (92.7)

3.2 COVID-19 vaccination status

A total of 204 participants were asked about their COVID-19 vaccination status. Of these, 190 (93.14%, 95% CI, 88.8%−95.9%) self-reported having received at least one dose of COVID-19 vaccine (Fig 2). Among the 147 participants who provided detailed vaccination information, most subjects were vaccinated with a single-dose of Ad26.COV2.S (n = 72, 49.0%), followed by a single dose of BNT162b2 (n = 29, 19.73%), while 6.12, 6.8, 10.2 and 4.08% subjects received two doses of ChAdOx1, BNT162b2, CoronaVac and mixed COVID-19 vaccines, respectively (Figure 2). A mixed dose regimen occurred when the first and second doses were of different vaccine brands. No booster dose was given to the vaccinees who completed a 2-dose BNT162b2 primary mRNA COVID-19 series. Based on the available vaccination information collected, the date of vaccine administration ranges from Sep 10 September 2021 to 28 September 2022.

3.3 Anti‑SARS‑CoV‑2 spike protein S1 IgG responses

Specific anti-S1 IgG levels were determined in all serum samples by ELISA at a dilution of 1:100 (Figure 3A). Within the cohort, 314 (69.78%) subjects had a positive anti-S1 IgG response. Anti-S1 IgG levels were significantly higher in the vaccinated group than in the unvaccinated and control groups (p < 0.01 and < 0.0001, respectively). No difference in anti-S1 IgG levels was observed between unvaccinated and control groups. However, 4 out of 14 non-vaccinated subjects showed a weak positive reaction. There was no difference in anti-S1 IgG levels between male and female vaccinees (p > 0.05) (Figure 3B) or between different age groups (p > 0.05 in all group comparisons) (Figure 3C). Among five villages, vaccinees in Bugoto and Bwondha had significantly higher IgG levels than those in Bukizibu (p < 0.0001) (Figure 3D). In the vaccinated group, anti-S1 IgG titer ranged from <100 to 1,600. Most COVID-19 vaccinees had a titer of 100 (33.68%), followed by 200 (29.47%), while 17.89% of vaccinated subjects had a titer below 100 (Figure 3E). Only 6.84, 10.53 and 1.58% of subjects had an anti-S1 IgG titer of 400, 800 and 1600, respectively.

3.4 Anti-S1 IgG responses in adolescents receiving a single dose of BNT162b2

Twenty-three (23) adolescents (aged 12-17 years) who received a single dose of BNT162b2 were stratified by faecal egg count (Supplementary Table S2). Anti-S1 IgG levels and titers measured two and a half months after vaccination showed no difference between KK positive (EPG> 0, n=14) and negative (EPG = 0, n=9) subjects (Figure 4A and B). However, IgG levels/titers were significantly lower in subjects with moderate- to heavy-intensity S. mansoni infection (n=5) compared to KK-negative subjects (p < 0.01 and < 0.05, respectively) (Figure 4C and D); whereas no difference was observed between subjects with a light infection (0<EPG<100, n=9, i.e., five individuals with S. mansoni infection, three individuals with hookworm infection, and one individual with S. mansoni and hookworm co-infection) and KK-negatives (n = 9). Within the sub-cohort, anti-S1 IgG antibody levels (OD values) and log-transformed IgG titers showed an inverse correlation with faecal egg counts determined by the KK method (r = -0.5477, p = 0.0068 and r = -0.4699, p = 0.0237, respectively) (Figure 4E and F).

3.5 Anti-S1 IgG isotypes in two vaccinated subgroups

Four IgG subclasses targeting the SARS-CoV-2 S protein were measured in 41 participants including subjects (n = 23) who received a single dose of BNT162b2 mRNA vaccine two and a half months prior to recruitment and individuals (n = 18) who were vaccinated with a single dose of Ad26.COV2.S about four months prior to sampling (Figure 5). All participants were positive for anti-S1 IgG1 antibodies in both vaccination groups, while three subjects and one individual were IgG3 positive in the groups receiving a single dose BNT162b2 and Ad26.COV2.S, respectively (Figure 5A and B).

SARS-CoV-2, a novel virus emerging in late 2019 that causes COVID-19, precipitated an unprecedented global health and economic crisis. The pandemic led to the rapid development and deployment of novel and effective COVID-19 vaccines. Following the global introduction of COVID-19 vaccination, it was important to assess the immunomodulatory effect of helminth infections on COVID-19 vaccine-induced immune responses and vaccine efficacy in LMICs [31, 32]. In Mayuge District, Eastern Uganda, S. mansoni and hookworms are the most common helminth species. The average schistosomiasis prevalence in the five study villages was 36.4%, which is higher than the national prevalence recorded in 2018 (26.5%) [23]. Three lakeshore villages, Bugoto, Bwondha and Musubi recorded similar prevalence (~50%), which was higher than Bukizibu (23%) and Igeyero (6%). The finding is consistent with the observation that S. mansoni prevalence rates were higher in communities located 5 km or less from the shores of Lake Victoria or Lake Albert than those located more than 5 km [33]. The prevalence data in the lakeshore villages were similar to a previous study conducted before the COVID-19 outbreak [34], suggesting that the pandemic did not significantly affect schistosomiasis transmission in these areas. The persistence of schistosomiasis in the villages despite prolonged mass drug administration (MDA) and education, was probably due to low MDA coverage and compliance as well as common misconceptions about schistosomiasis [35, 36].

There have been few studies to assess COVID-19 coverage and serum antibodies to SARS-CoV-2 spike protein in rural communities with co-endemic helminth infections. Here, we assessed COVID-19 vaccination status, uptake of different COVID-19 vaccine brands, and IgG antibody responses to SARS-CoV-2 spike S1 protein in 204 villagers who participated in a cross-sectional helminth survey in Mayuge District. One hundred and ninety of the 204 individuals who participated in the vaccination survey received at least one dose of COVID-19 vaccine, indicating a high vaccination coverage in the cohort. The highest uptake was recorded for the single-dose Ad26.COV2.S vaccine (72/147, 49%) followed by the BNT162b2 vaccine (one dose, 19.7%; two doses, 6.8%). The uptake of the other vaccines was low (about 4-8%). The variability in uptake of different COVID-19 vaccine brands may be due to personal preference or vaccine availability at the immunization clinics. Although there was a high acceptance rate, 81% of COVID-19 vaccinees had anti-S1 IgG titers ≤ 200, indicating that the antibody levels had declined in most vaccinees by the time of sampling. The majority of participants had not completed the two-dose primary BNT162b2 mRNA vaccination series. The low antibody levels and rapid decline probably underscore the overall impact of helminth infections on the performance of all vaccines and the importance of receiving the second dose of two-dose COVID-19 vaccines. Four of the 14 unvaccinated participants had positive albeit low anti-S1 IgG antibodies. At the time of the study, the national COVID-19 prevalence in Uganda was low (0.3%) and the incidence of SARS CoV-2 infection may be even lower in rural areas than in urban areas. Thus, the weak IgG positivity in these unvaccinated individuals is more likely due to cross-reactivity to common cold coronaviruses circulating in the region [6, 37, 38], rather than pre-existing antibodies from a previous SARS-CoV-2 infection. A recent study also reported the presence of pre-existing CD4⁺ and CD8⁺ T-cell responses to SARS-CoV-2 in stored peripheral blood mononuclear cells (PBMC) from Ugandans who had never been exposed to SARS-CoV-2 infection [3].

In participants who received a single dose of BNT162b2 vaccine within a narrow time window (Supplementary Table S2), an inverse correlation was observed between faecal egg counts and antibody titer levels. Subjects with a moderate-to-heavy S. mansoni burden had significantly lower anti-S1 IgG levels/titers compared to KK-negative individuals. The results indicate an impaired humoral immune response to the BNT162b2 vaccine in the group with an EPG>100. Participants with light S. mansoni and/or hookworm infections also showed a declined trend in anti-S1 IgG level compared to KK-negatives, but the difference between the two groups was not statistically significant based on the current sample size (Fig 4C, p = 0.0739). These results together with the correlations between anti-S1 IgG antibody levels/titers and faecal egg counts, suggest an infection intensity-dependent immunomodulatory effect on the immune responses elicited by COVID-19 vaccines. Our results are thus at least partially consistent with those of previous studies, e.g., Musaigwa et al showed that chronic S. mansoni infection can reduce the persistence of antibody responses in humans and mice immunised with poliovirus vaccines [39]. Similarly, schistosome infection also negatively affects antibody levels/titers after Hepatitis B (HepB) vaccination [17, 40]. In contrast, it has been recently shown that infection with Heligmosomoides polygyrus bakeri, a gastrointestinal-restricted murine hookworm, has limited effects on B cell responses induced by an mRNA vaccine against SARS-CoV-2 [41]. Nevertheless, the potential mechanisms responsible for the feeble antibody responses to the S1 protein in vaccinated participants with moderate-to-heavy schistosome infection are not known. Possible underlying mechanisms include: i) Chronic schistosome infection, which typically induces a polarised Th2 immune response, creating a cytokine environment that potentially suppresses T follicular helper (Tfh) responses, which are critical for providing ‘B-cell help’ in response to vaccination [17]. ii) S. mansoni infection can potentially induce death of antibody-producing plasma cells in the bone marrow [39]. Further mechanistic studies are needed to address this issue. Nevertheless, there is also accumulating evidence that deworming could enhance/restore the immune response to vaccines against a variety of pathogens [39, 42, 43]. To ensure adequate immune protection, adults infected with schistosomes should receive a complete 2-dose BNT162b2 primary mRNA COVID-19 series. A ‘treat and vaccinate’ strategy of treatment with praziquantel (PQZ) could also be implemented in these individuals prior to vaccination.

This study has several limitations. Firstly, the small sample size and cross-sectional design of the study did not allow us to perform statistical modelling to adjust for potential confounders (e.g. age, sex, vaccine type, and helminth species) nor to undertake multiple correction testing. Secondly, blood sampling at only one time point probably missed important changes in serum antibody concentrations during the post-vaccination period. In addition, sample collection during the survey occurred at different times but not at a standard time point post-vaccination. Thirdly, no previous exposure to common cold coronaviruses has been investigated in the study. We cannot completely rule out the possibility that some of the anti-S1 IgG responses detected in the cohort studied are due to a previous common hCoV infection [6, 38]. Finally, we cannot conclude whether the observed antibody responses induced by single-dose COVID-19 vaccination provides protection because we did not assess the functional activity of the antibodies in a virus neutralisation assay.

The outbreak of COVID-19 did not significantly alter the prevalence of schistosomiasis in three lakeshore villages in Mayuge District. Our study confirmed that the acceptance rate of COVID-19 vaccination in these schistosomiasis-endemic areas was high at the time of investigation but anti-S1 IgG levels and titers in these vaccinees were low. Moderate-to-heavy schistosome infections suppressed COVID-19 vaccine-induced antibody responses in a subgroup of participants who received a single dose of BNT162b2. However, these results need to be validated in other studies with larger sample sizes in different endemic settings. Our findings therefore call for further research on the immunomodulatory effect of helminth infections on the efficacy of COVID-19 vaccination, which may inform the implementation of a ‘treat and vaccinate’ policy in LMICs with a heavy helminth burden.

Ethical statement

Ethical approval for the study was obtained from the Institutional Review Board, Vector Control Division, Ministry of Health, Uganda (IRB number VCDREC160) and the Human Ethics Committee of QIMR Berghofer Medical Research Institute (QIMRB) (P3700). Written informed consent was obtained from all participants (for individuals under 18 years of age, consent was obtained from their legal guardians prior to the administration of survey and sampling).

Authors’ contributions

DPM and PC formulated the research aims and prepared the study protocol. PC supervised the research. MA, RC, MKJ, DPM, TGE and PC provided study materials. MN, YM, MA, RC, TGE and PC developed the methodology, and collected and analysed the data. MN, YM, TGE and PC drafted the original manuscript. MKJ, TGE and PC critically reviewed and edited the manuscript. The authors read and approved the final version of the manuscript.

Funding

This work was supported by an Australian Infectious Disease Research Centre Seed Grant, a QIMR Berghofer Seed Grant and grants (APP1160046, APP2008433, and APP1194462) from the National Health and Medical Research Council (NHMRC) of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgements

We thank all study participants who provided samples and acknowledge the hard work and dedication of the local field and clinical staff who collected samples and conducted field studies. We thank Dr Xianyu Piao (Institute of Pathogen Biology, Chinese Academy of Medical Sciences) for providing serum samples from healthy Chinese donors.

Conflict of interests

The authors declare no conflict of interests.

Data availability statement

All data supporting the findings of this study are available within the paper and its Supplementary Information.

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The authors declare no competing interests.

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COVID-19 vaccination survey and anti-SARS-CoV-2 S1 IgG responses in a human cohort from Schistosoma mansoni-endemic villages in Mayuge, Uganda: A cross-sectional study

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Abstract

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1. Introduction

2. Methods

2.1 Ethics

2.2 Study design and period

2.3 Setting

2.4 Study population

2.5 Data and sample collection

2.6 Serological analyses

2.7 Statistical analysis

3. Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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