Introduction
Malaria and hookworm are important parasitic diseases in humans, in terms of socio-economic impact and public health importance. Malaria is typically an acute disease; however, chronic asymptomatic infections may persist, particularly in adults living in endemic areas. Hookworm infection on the other hand is mainly chronic. In areas where these parasites are co-endemic and the transmission rates are high, co-infection is very common and this may influence morbidity and immune response against these infections [
1‐
4], with possible implications on vaccine efficacy. The GMZ2 malaria vaccine candidate is a recombinant fusion protein, containing two blood-stage antigens of
P. falciparum, GLURP R0 and MSP3 [
5]. Previous phase 2 clinical trial of GMZ2 showed it well tolerated and immunogenic albeit with modest efficacy [
5]. This is not uncommon since most malaria vaccine candidate efficacy trials in Africa has so far not been remarkably efficacious against malaria [
6‐
11]. However, factors modulating immune responses against malaria vaccine candidates that may help provide possible explanations to the sub-optimal efficacies observed are not well understood. Helminths secrete immunomodulatory molecules to selectively skew or dampen immune responses to promote their long-term survival [
12]. Hookworm infection is associated with higher levels of IL-10 and lower levels of both Th1 and Th2 cytokines [
13]. The enhanced IL-10 production may be a mechanism to regulate pathology due to inflammatory responses elicited by the infection Hookworm infection is very common in Africa, however its effect on malaria vaccine candidate antigens such as GMZ2 have not been extensively investigated.
Treatment of infected people with anthelmintic drug may alter antimalarial specific immune responses [
1,
2,
14,
15]. Since albendazole treatment is administered to hookworm infected people who may be living in malaria endemic communities (exposed to both malaria and hookworm), it is important to determine if this chemotherapy alters any of the responses to malaria vaccine candidate antigens and inadvertently affect vaccine efficacy. We have previously shown that in the absence of other helminths, co-infection of hookworm with
P. falciparum may modulate blood parasitemia levels and cytokine responses [
16]. Different helminths modulate the immune response to malaria differently.
Trichuris trichiura infections in malaria patients was associated with reduced antibody levels against
P. falciparum antigens [
3]. Similarly, Courtin et al., [
17] found
Schistosoma haematobium infection to be associated with reduction in IgG levels against
P. falciparum antigens MSP-1 and GLURP. Gabonese children infected with
Ascaris lumbricoides had a significantly higher
P. falciparum anti-gametocyte antibody levels compared to non-infected children [
4]. Interestingly,
T. trichiura infection was associated with lower
P. falciparum anti-gametocyte antibody levels in the same study [
4]. To date, hookworm modulation of the antibody responses against malaria vaccine antigens has not been explored. Thus, the current study aimed to investigate the effect of hookworm infection and anthelmintic treatment on antibody responses against the GMZ2 vaccine and its constituent antigens in a population co-endemic with both parasites
.
Discussion
Concurrent infection with malaria and hookworm is common among people living in Kintampo North Municipality, and this may affect immune responses and clinical outcomes of these infections. The immune responses to hookworm infection may have a “bystander” effect on antimalarial immunity. In this study IgG1, IgG3 and IgM responses to the GMZ2 malaria vaccine candidate and constituent antigens were studied before and after anthelmintic treatment with albendazole.
Our result showed that the co-infected individuals had higher levels of IgG3 antibodies against GMZ2 and IgG1 against GLURP R0. These antibodies are known to be associated with protection against malaria [
1,
23‐
25].
Ascaris lumbricoides co-infection with malaria were also found to show an increased anti-gametocyte immune response compared to the uninfected participants [
4]. These findings suggest that the presence of the
N. americanus worm may boost the antimalarial specific IgG1 and IgG3 antibody responses against malaria. This is supported by our previous findings that
P. falciparum parasitaemia was lower in co-infected individuals compared to those with mono-infections [
16]. However, our findings conflict with other helminth-malaria parasite co-infection study by Courtin et al. [
26], who found
Schistosoma haematobium infection led to significant reduction in
Plasmodium falciparum-specific IgG responses levels directed to MSP-1 and to GLURP antigens. Another study in Zimbabwe, rather reported no association between Schistosoma infection and humoral response to malaria parasites [
27]. Furthermore, Esen et al. [
28], found significantly lower antibody response against GMZ2 and GLURP antigens after vaccination with the malaria vaccine candidate GMZ2 in individual who had
T. trichiura present during vaccination. The observation from these studies indicate that helminths co-infection with
P. falciparum may have varying antibody production against malaria antigens. These variations in the findings could be due to the differences in the biology and the anatomical position of the adult worms in the host, difference in the age of study participants and study design.
The study found no significant association with antibody response against MSP3 antigen in the co-infected individual, this corroborate with studies by M Esen, B Mordmuller, PM de Salazar, AA Adegnika, ST Agnandji, F Schaumburg, AB Hounkpatin, S Bruckner, M Theisen, S Belard, et al. [
3], who reported no significant effect of
T. trichiura on anti-MSP3 antibody concentration. Presumably, MSP3 may be the less immunogenic part of the vaccine [
29,
30].
The study found a significantly positive association between the antibody levels (IgG3, and IgM) and age against GMZ2, and constituent antigens. This finding is consistent with studies by K Marsh, RH Hayes, DC Carson, L Otoo, F Shenton, P Byass, F Zavala and BM Greenwood [
31] who reported a positive correlation between antibody titers and age, D Dodoo, A Aikins, KA Kusi, H Lamptey, E Remarque, P Milligan, S Bosomprah, R Chilengi, YD Osei and BD Akanmori [
25] and B Adu, MK Cherif, S Bosomprah, A Diarra, FK Arthur, EK Dickson, G Corradin, DR Cavanagh, M Theisen, SB Sirima, et al. [
18], also reported high levels of IgM against MSP3 and GLURP with age among Ghanaian children. These results are consistent with the hypothesis that immunity to malaria is largely effected through antibody-mediated mechanisms and that protective antibody levels to relevant antigens increase with age of an individual co-infected with other parasites [
32]. The weak association observed between antibody levels and age in our study population may be due to the fact that most of the study participants were older and may have greater cumulative exposure to the malaria parasite with already developed acquired immunity compared to children [
33].
The IgG1 and IgG3 antibody levels measured against GMZ2, were significantly decreased after albendazole treatment. Also, IgG3 response to GLURP R0 and IgG1 and IgM responses to MSP3 were significantly decreased after treatment. Helminth infections are usually associated with a predominantly Th2-type of immune response [
34]. In our previous study, we observed an increased level of IL10 in
P. falciparum and
N. americanus co-infection, which significantly decreased after successful albendazole, treatment [
16]. Since IL10 is known to provide help for B cells to produce antibodies [
26], this may explain both the increased malarial antibodies in co-infected individuals and the decrease in antibody levels observed after hookworm treatment.
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