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REVIEW ARTICLE
The effect of helminth infection on vaccine responses
in humans and animal models: A systematic review
and meta-analysis
Agnes Natukunda
1,2
| Ludoviko Zirimenya
1
| Jacent Nassuuna
1
|
Gyaviira Nkurunungi
1,3
| Stephen Cose
1,4
| Alison M. Elliott
1,4
| Emily L. Webb
2
1
Immunomodulation and Vaccines Programme,
MRC/UVRI and LSHTM Uganda Research
Unit, Entebbe, Uganda
2
MRC International Statistics and
Epidemiology Group, Department of Infectious
Disease Epidemiology, London School of
Hygiene and Tropical Medicine, London, UK
3
Department of Infection Biology, London
School of Hygiene and Tropical Medicine,
London, UK
4
Department of Clinical Research, London
School of Hygiene and Tropical Medicine,
London, UK
Correspondence
Agnes Natukunda, Immunomodulation and
Vaccines Programme, MRC/UVRI and LSHTM
Uganda Research Unit, Entebbe, Uganda.
Email: agnes.natukunda@mrcuganda.org;
natukundagnes@yahoo.com
Funding information
Medical Research Council, Grant/Award
Number: MR/R02118X/1
Abstract
Vaccination has potential to eliminate infectious diseases. However, parasitic
infections such as helminths may hinder vaccines from providing optimal protection.
We reviewed existing literature on the effects of helminth infections and their treat-
ment on vaccine responses in humans and animals. We searched literature until
31 January 2022 in Medline, EMBASE, Global health, Scopus, and Web of science;
search terms included WHO licensed vaccines and human helminth types. Standard-
ized mean differences (SMD) in vaccine responses between helminth infected and
uninfected or anthelminthic treated and untreated individuals were obtained from
each study with suitable data for meta-analysis, and combined using a random effects
model. Analysis was stratified by whether helminth exposure was direct or prenatal
and by vaccine type. This study is registered with PROSPERO (CRD42019123074).
Of the 4402 articles identified, 37 were included in the review of human studies and
24 for animal experiments. For human studies, regardless of vaccine type, overall
SMD for helminth uninfected/treated, compared to infected/untreated, was 0.56
(95% CI 0.04–1.07 and I
2
=93.5%) for direct helminth exposure and 0.01 (95% CI
0.04 to 0.07 and I
2
=85.9%) for prenatal helminth exposure. Effects of anthel-
minthic treatment were inconsistent, with no overall benefit shown. Results differed
by vaccine type, with responses to live vaccines most affected by helminth exposure.
For animal studies, the most affected vaccine was BCG. This result indicates that
helminth-associated impairment of vaccine responses is more severe for direct, than
for prenatal, helminth exposure. Further research is needed to ascertain whether
deworming of individuals before vaccination may help improve responses.
KEYWORDS
helminths, immunity, meta-analysis, systematic review, vaccines
Received: 1 April 2022 Revised: 20 May 2022 Accepted: 14 June 2022
DOI: 10.1111/pim.12939
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2022 The Authors. Parasite Immunology published by John Wiley & Sons Ltd.
Parasite Immunol. 2022;e12939. wileyonlinelibrary.com/journal/pim 1of10
https://doi.org/10.1111/pim.12939
1|INTRODUCTION
Prevention of diseases through vaccination continues to be a major
global health focus and the recent SARS-CoV-2 pandemic has further
brought this to international public attention. The World Health Orga-
nization (WHO) estimated that in 2019, global immunization coverage
for diseases such as polio, measles and diphtheria-tetanus-pertussis
had surpassed 70%.
1
Although global vaccine coverage is on the rise
including in low- and middle-income countries, efficacy and immuno-
genicity of some vaccines varies greatly by population and geographic
location, with impaired responses reported in low-versus high-income
and rural versus urban settings.
2–4
These settings are characterized by
high exposure to infections, including parasites such as helminths and
malaria.
5,6
Exposure to parasitic infections has been proposed to play
a role in modulating vaccine immune responses.
7
Immunomodulation by helminths has been tested for several vac-
cines in both humans
8,9
and animal models.
10–12
Many of these stud-
ies have reported that vaccine-specific immune responses may be
impaired due to the presence of these infections prior to vaccination.
However, some studies have reported improved tetanus, HPV and
polio immune responses in individuals exposed to helminths or malaria
infections,
13–15
indicating that the effect of these infections on
immune responses may vary by vaccine type and individual. There-
fore, understanding the effect of helminths on how humans and ani-
mals respond to vaccines is an important topic that may have global
health policy implications.
The effect of helminth infections on immunization responses has
been previously reviewed.
16,17
The most recent review combined data
from both human studies and animal experiments for all vaccine types
and concluded that immune responses to vaccines were negatively
affected by presence of ‘parasitic’infections, defined to include hel-
minths, protozoa, bacteria and viruses. Interpretation of these com-
bined results is challenging, since humans may respond differently to
parasite exposure than animals, and animal experiments are a more
controlled environment. Furthermore, effects may differ depending
on the vaccine type. The review highlighted the significance of
chronic, rather than acute helminth infections, and evidence of a
greater effect on T-cell dependent vaccines. Elsewhere it is proposed
that parasitic infections may be more likely to affect responses to live,
than inert, vaccines
4
; responses to orally administered vaccines may
also be easily modulated compared to parenterally administered vac-
cines.
18
Why some vaccine responses are more affected than others
is not fully known, however, helminths may, for example, trigger
innate immune response profiles that change how the immune system
responds to live vaccines.
19
The previous review did not examine the effect of prenatal expo-
sure to ‘parasitic’infections on vaccine responses.
16
We cannot fully
assess the effects of exposure to helminths without assessing effects
of prenatal helminth exposure since a significant number of vaccina-
tions happen between birth and 1 year of age when children are less
likely to be individually exposed to helminths. Therefore, reviewing
existing evidence on the effect of prenatal exposure to helminths on
vaccine responses is important.
The objective of this work was to search, review and summarize
existing literature on the effect of helminth infections and/or their
treatment on vaccine responses in human and animal models sepa-
rately, assess whether the direction of modulation is vaccine-specific
and assess the effects of both direct helminth exposure and in utero
helminth exposure. The purpose of this work was to inform public
health policy and identify potential interventions that could improve
vaccine effectiveness.
2|MATERIALS AND METHODS
2.1 |Search strategy and selection criteria
The review and meta-analysis were conducted and reported according
to PRISMA guidelines.
20
Literature searches were conducted up to
31 January 2022 in Medline, EMBASE, Global health, Scopus and
Web of Science with no start date limit. The search terms targeted
articles reporting the effect of helminths or their treatment on vaccine
responses and included all human helminth species and WHO-
licensed vaccines (Appendix 1 in Supporting Information). All retrieved
articles from the database searches were exported to Mendeley soft-
ware for further management. We further searched bibliographies to
identify articles that were not captured during the database search.
In the first stage, titles and abstracts of retrieved articles were
screened for potential inclusion by two reviewers (AN and LZ) for
human studies and two reviewers (GN and JN) for animal studies. The
second stage involved reviewing full texts of articles deemed relevant
in stage one with the same pairs of reviewers. In both stages, articles
were independently reviewed for inclusion by each of the two
reviewers; in case of disagreement a third reviewer (EW) was involved
to discuss discrepancies and reach consensus. Studies were included
in the qualitative and quantitative review if they compared immune
responses to a vaccine between helminth infected and uninfected
groups or between anthelminthic treated and untreated groups; and if
helminth status of study participants was laboratory diagnosed before
vaccination and an immunological outcome measured thereafter.
Studies were included in the quantitative synthesis if data suitable for
a meta-analysis were reported in the article or made available upon
contacting the author. Articles were excluded if the status of helminth
infection was not determined or was determined after vaccination
had occurred, or if there was no comparative control group or if they
described case series. The review included both intervention and
observational studies. The review protocol is registered at www.crd.
york.ac.uk/prospero, CRD42019123074.
21
2.2 |Data analysis
Data from relevant articles were extracted from text, tables and fig-
ures (using web plot digitizer version 4.4
22
) into a Microsoft Excel data
extraction tool we designed specifically for this purpose. For articles
where data extraction failed, authors were contacted to provide the
2of10 NATUKUNDA ET AL.
relevant data. Data extracted included study and participant charac-
teristics, vaccines and helminth species, and immunological outcomes.
Duplicate articles missed during the automated deduplication process
in Mendeley software were identified and excluded at this stage.
We used the Effective Public Health Practice Project tool
(EPHPP)
23
to assess quality of individual human studies. With this
tool, studies were rated as strong, moderate or weak based on an
eight-component checklist. The SYRCLE
24
risk of bias tool was used
for animal experiments where studies were rated as having low, high
or unclear risk of bias on 10 components. Details of the items scored
are in Appendices 2 and 3 in Supporting Information.
The primary outcome for our review was immune response to
vaccines. For relevant articles, we extracted a narrative summary of
main findings which included all immune parameters reported on in
the articles. For the purpose of quantitative synthesis, mean (SD),
median (IQR) and geometric mean (95% CI) were extracted separately
by helminth infection or treatment status. Summary measures other
than mean (SD) were converted to mean (SD) on the log
10
scale.
25,26
Where studies reported on multiple immune parameters for the same
vaccine, we chose the parameter that is thought to be the best corre-
late of protection for that vaccine. When the outcome of interest was
reported at multiple time points, a weighted average across time
points was obtained as a single measure for that study.
27
Since studies reported several vaccine-specific immune responses
and on different units and scales, standardized mean differences
(SMD) between helminth infection and/or treatment groups with 95%
confidence intervals were calculated for each study using Hedges' g.
28
We hypothesised that in addition to the sampling variability that
exists within studies, the effect of helminths on vaccine responses
would be likely to vary from study to study, therefore, study specific
SMDs were averaged into an overall effect size and 95% confidence
interval using a random effects model with restricted maximum likeli-
hood estimation, to account for between study variability. The hel-
minth infected/anthelminthic untreated group was used as the
reference category, therefore an SMD of >0 represents higher
response in the uninfected versus infected, or in the treated versus
untreated group. I
2
statistic was used to quantify the amount of het-
erogeneity among study-specific SMDs. It ranges between 0% to
100%, with 0% indicating no heterogeneity between study specific
SMDs.
29
Analysis was conducted separately by whether the study
reported the effect of direct or prenatal exposure to helminth infec-
tion. For direct helminth exposure, individuals are considered to be
directly infected with helminths; prenatal exposure is where the sub-
ject is exposed to helminths in utero. Subgroup analyses by vaccine
type (separately for direct versus prenatal helminth exposure) were
conducted to estimate vaccine-specific SMDs. As a secondary analy-
sis, we present data comparing vaccine responses among helminth
uninfected versus infected, and anthelminthic treated versus
untreated individuals to evaluate whether the direction of effects of
being helminth uninfected and receiving anthelminthic treatment
were consistent. Further, sensitivity analysis was done by excluding
studies that had extremely small or large effect sizes and/or very small
sample sizes. Publication bias was assessed using funnel plots with
Egger's test being used to test for funnel plot symmetry. Analysis was
done using Stata meta-analysis suite ‘meta’in Stata version 16.
3|RESULTS
3.1 |Human studies
Article eligibility screening results and reasons for exclusion are pre-
sented in Figure 1. The search identified 2184 unique articles. Of
these, 37 (19 from randomized controlled trials) were included in the
qualitative review of human studies. Data suitable for meta-analysis
for human studies was available for 27 articles reporting data from
23 studies. Of these, 13 articles evaluated the effect of direct hel-
minth exposure/treatment on vaccine responses and 14 the effect of
prenatal helminth exposure/treatment on vaccine responses. Articles
included in the human review and meta-analysis were from research
conducted in Africa, Asia and South America and were published
between 1983 and 2021. Relevant articles reported data on a total of
14 vaccines with many articles reporting data on multiple vaccines:
BCG (11 articles), tetanus toxoid (14), diphtheria (6), influenza (7), hep-
atitis B (7), pertussis (2), measles (6), polio (3), meningococcal (1),
pneumococcal (2), oral typhoid (2), cholera (1), rubella (1) and rotavirus
(1). Since we hypothesised different effects on different vaccine
types, results are presented separately for each vaccine. For each of
the vaccines included in the meta-analysis, details of study-specific
SMDs, their contribution to the overall SMD and heterogeneity mea-
sure (I
2
) are presented in Appendix 4 in Supporting Information for
direct helminth exposure and Appendix 5 in Supporting Information
for prenatal helminth exposure. A narrative summary of findings
including study characteristics and references from human studies is
presented in Appendix 6 in Supporting Information.
Of 11 articles that reported on BCG, four reported on the effect
of direct helminth exposure on vaccine responses and three of
these were eligible for meta-analysis. The meta-analysis results show
evidence of higher immune responses to BCG among helminth
uninfected compared to infected individuals (SMD 0.72, 95% CI 0.34
to 1.09) (Figure 2). The fourth article whose data was not suitable for
meta-analysis also reported higher responses in persons uninfected
with Onchocerca volvulus
30
(Appendix 6 in Supporting Information).
Seven articles contributing nine effect sizes were included in both the
narrative summary and the meta-analysis for prenatal helminth expo-
sure and the average effect size was SMD 0.54, 95% CI 0.32 to 1.40
(Figure 3). Since this analysis included two articles from the same
study that reported the same outcomes at 1 year
31
and 5 years,
32
a
sensitivity analysis excluding results from the year five outcomes arti-
cle was done and resulted in an average estimate of SMD 0.73, 95%
CI 0.42 to 1.88. Heterogeneity was moderate for direct helminth
exposure (I
2
=31%) (Appendix 4 in Supporting Information) and large
for prenatal exposure (I
2
=99%) (Appendix 5 in Supporting
Information).
Of 14 articles that reported on tetanus toxoid, seven reported on
the effect of direct helminth exposure on vaccine responses and five
NATUKUNDA ET AL.3of10
of these were eligible for meta-analysis. Meta-analysis results show
no overall significant helminth effect on TT responses (SMD 1.03,
95% CI 0.75 to 2.81 and I
2
=98%) (Figure 2). Two articles not
included in the meta-analysis reported significant higher antibody
responses in helminth uninfected compared to infected individ-
uals.
33,34
The average effect size for association between prenatal hel-
minth exposure and TT responses among six articles contributing
seven effect sizes was (SMD 0.02, 95% CI 0.10 to 0.05 and
I
2
=39%) (Figure 3). One article not included in the meta-analysis
reported no effect of prenatal anthelminthic treatment on TT
responses.
All six relevant articles on diphtheria contributing seven effect
sizes were included in the meta-analysis and all were investigating the
effect of prenatal helminth exposure. Of these, five effect sizes came
from studies that looked at the effect of prenatal helminth exposure
and two effect sizes were from a study that evaluated effect of prena-
tal treatment of helminths on vaccine responses. The two effect sizes
from this study resulted from two independent randomisations of
treatment with albendazole versus placebo and treatment with prazi-
quantel versus placebo.
31
Overall, the average effect was (SMD 0.06,
95% CI 0.02 to 0.14 and I
2
=43%) (Figure 3).
Among seven articles that reported on influenza vaccine, one arti-
cle reported on direct helminth exposure and found that treatment of
helminths before vaccination was not significantly associated with
vaccine specific immune responses to influenza vaccine.
35
The aver-
age effect for the five articles reporting on prenatal helminth exposure
was SMD 0.03, 95% CI 0.06 to 0.12 and I
2
=52% (Figure 3). The
sixth article not included in the meta-analysis reported higher titers at
12 months among children of uninfected mothers compared to
infected untreated and infected treated groups; no significant differ-
ences were observed at 6 months.
36
In seven studies on Hepatitis B, meta-analysis of results averaged
from two studies reported higher responses among helminth unin-
fected individuals (SMD 1.69, 95% CI 0.15 to 3.23 and I
2
=94%)
(Figure 2). One study not included in the meta-analysis found no sig-
nificant difference in anti-hepatitis B titers between helminth infected
Records identied through
database searching
Medline (n=1236)
EMBASE (n=2468)
Global health (n=2328)
Scopus (n=934)
Web of science (n=604)
gnineercS
ded
u
lcnI
ytilibigilE
noitacifitned
I
Additional records identied
through other sources
(n=1)
Records after duplicates removed
(n=4402)
Records screened
Human (n=2184)
Animal (n=2218)
Records excluded
Human (n=2057)
Animal (n=2134)
Full-text articles
assessed for eligibility
Human (n=127)
Animal (n=84)
Full-text articles excluded
Human (n=90): Abstracts which
were later published as articles (10),
presented results from same study (1),
helminth status after vaccination (15),
Unlicensed vaccines (5), no
vaccination done (15), outcome not
vaccine responses (8), no data
presented (6), no comparison by
helminth status (8), Protocol papers
(4), animal papers (3), pilot study (1),
editor correspondences (3), workshop
report (1), review paper (4), no access
to full article (6).
Animal (n=60): Abstracts which
were later published as articles (1),
No comparison by helminth status
(7), helminth status after vaccination
(7), outcome not vaccine responses
(9), Review paper (1), Unlicensed
vaccines (21), Report (1), no
helminth infection (2), no vaccination
done (7), no control group (2), no
access to full article (2).
Articles included in
qualitative synthesis
Human (n= 37 )
Animal (n=24)
Articles included in
quantitative synthesis
(meta-analysis)
Human (n=27)
FIGURE 1 Flow diagram of study
selection and screening
4of10 NATUKUNDA ET AL.
BCG
Tetanus Toxoid
Hepatitis B
H.Influenza
Measles
Polio
Meningococcal
Cholera
Uninfected vs infected
Treated vs untreated
Vaccine
Comparisons
Overall
Test of group differences: Qb(7) = 29.78, p = 0.00
Test of group differences: Qb(1) = 1.08, p = 0.30
3
5
2
1
1
1
1
1
9
6
Number of effect size
Better responses (infected/untreated) Better responses (uninfected/treated)
-2 0 2 4
SMD 95% CI
0.72 (
1.03 (
1.69 (
-0.09 (
0.53 (
-0.88 (
0.13 (
-0.03 (
0.83 (
0.28 (
0.56 (
0.34,
-0.75,
0.15,
-0.52,
0.15,
-1.47,
-0.28,
-0.50,
-0.15,
-0.05,
0.04,
1.09)
2.81)
3.23)
0.34)
0.90)
-0.28)
0.54)
0.43)
1.81)
0.62)
1.07)
0.000
0.257
0.032
0.685
0.006
0.004
0.537
0.883
0.096
0.097
0.033
P-value
FIGURE 2 Forest plot of the effect of direct helminth infection or anthelminthic treatment on vaccine responses. References and study
specific standardized mean differences are presented in Appendix 4 in Supporting Information.
BCG
Tetanus Toxoid
Diphtheria
H.Influenza
Hepatitis B
Pertussis
Measles
Polio
Rubella
Rotavirus
Uninfected vs infected
Treated vs untreated
Vaccine
Comparisons
Overall
Test of group differences: Qb(9) = 213.25, p = 0.00
Test of group differences: Qb(1) = 0.93, p = 0.34
9
7
7
6
5
3
6
2
1
1
30
17
Number of effect sizes
Better responses (infected) Better responses (uninfected)
-1 0 1 2
SMD 95% CI
0.54 (
-0.02 (
0.06 (
0.03 (
-0.03 (
0.08 (
0.14 (
-0.24 (
0.07 (
-0.70 (
0.06 (
-0.00 (
0.01 (
-0.32,
-0.10,
-0.02,
-0.06,
-0.11,
0.01,
-0.07,
-0.33,
-0.02,
-0.80,
-0.05,
-0.03,
-0.04,
1.40)
0.05)
0.14)
0.12)
0.06)
0.14)
0.36)
-0.14)
0.17)
-0.60)
0.17)
0.03)
0.07)
0.216
0.550
0.142
0.509
0.539
0.021
0.181
0.000
0.144
0.000
0.318
1.000
0.620
P-value
FIGURE 3 Forest plot of the effect of prenatal helminth infection or anthelminthic treatment on vaccine responses. References and study
specific standardized mean differences are presented in Appendix 5 in Supporting Information.
NATUKUNDA ET AL.5of10
and uninfected individuals.
37
Among the four studies investigating
prenatal exposure to helminths, there was no overall association with
Hepatitis B responses (SMD 0.03, 95% CI 0.11 to 0.06 and
I
2
=21%) (Figure 3).
Among six articles that reported on measles, we identified only
one article on direct helminth exposure which reported significantly
higher responses among helminth uninfected compared to infected
individuals 1 week after immunization and no significant difference at
24 weeks post immunization.
38
Six effect sizes from five articles were
included in the meta-analysis for the effect of helminth infection on
responses to measles among children exposed to helminths prenatally.
The average effect size was (SMD 0.14, 95% CI 0.07 to 0.36 and
I
2
=92%) (Figure 3). One of these studies contributed two effect sizes
to the meta-analysis; one effect size for treatment with albendazole
versus placebo and the other for treatment with praziquantel versus
placebo.
31
The effect of prenatal helminth exposure on responses to pertus-
sis vaccine was reported in two articles. The average effect size was
(SMD 0.08, 95% CI 0.01 to 0.14 and I
2
=14%). One article each iden-
tified for rubella,
15
meningococcal
39
and cholera
39
vaccines showed
no association with helminth infection status. We found one article
on the effect of direct helminth exposure on live, oral polio vaccine
which reported lower responses among uninfected compared to
infected individuals.
40
Similarly, findings from two articles reporting
on the effect of prenatal helminth exposure on live, oral polio vaccine
suggested lower responses among children of mothers without hel-
minths (SMD 0.24, 95% CI 0.33 to 0.14 and I
2
=0.01%). The
only study we found on live, oral rotavirus also reported significantly
lower response levels in children born to helminth uninfected com-
pared to infected mothers.
15
As an exploratory analysis, we computed overall SMDs separately
for articles reporting on the effect of helminth infection and articles
reporting on the effect of anthelminthic treatment. We found that
there was no significant difference in vaccine responses between hel-
minth infected and uninfected (SMD 0.83, 95% CI 0.15 to 1.81) or
anthelminthic treated and untreated (SMD 0.28, 95% CI 0.05 to
0.62). When the overall SMD resulting from articles reporting on the
effect of helminth infection was compared to the overall SMD from
articles reporting on the effect of anthelminthic treatment, there was
little statistical evidence for a difference between the two overall
SMDs (p=.30) (Figure 2). For prenatally helminth exposed children,
there was no significant difference in vaccine responses between hel-
minth infected and uninfected (SMD 0.06, 95% CI 0.05 to 0.17) or
anthelminthic treated and untreated (SMD 0.00, 95% CI 0.03 to
0.03) groups and there was no statistical evidence for a difference
between the two overall SMDs (p=.34) (Figure 3). Overall, combining
results from all vaccines, we found significantly higher vaccine
responses among direct helminth uninfected/treated compared to
helminth infected/untreated individuals (SMD 0.56, 95% CI 0.04 to
1.07 and I
2
=93.5%) (Appendix 4 in Supporting Information) and no
significant association of prenatal helminth infection/treatment with
vaccine responses (SMD 0.01, 95% CI 0.04 to 0.07 and I
2
=85.9%)
(Appendix 5 in Supporting Information).
3.2 |Animal studies
The database search identified 2218 unique animal experiment arti-
cles and of these 24 articles were included in this review (Figure 1).
Identified relevant articles assessed the effect of helminths on BCG
(11 articles), tetanus toxoid (2), diphtheria (1), influenza (2), hepatitis B
(2), pertussis (1), pneumococcal (1), HPV (1), yellow fever (1), cholera
(1) and rabies (1). Reviewed articles were published between 1969
and 2021. For animal experiments, a meta-analysis was not done due
to few studies per vaccine type. A narrative summary of results
including study characteristics and references of articles for animal
experiments is presented in Appendix 7 in Supporting Information.
Of the 11 articles that presented data on BCG, 10 reported a
reduction in some form of BCG response among helminth infected
compared to uninfected animals. Responses reported in these studies
included antibody and cytokines,
10,41–44
mycobacterial clearance in
the lungs,
45
lymph node expansion,
46
hypersensitive footpad
swelling,
47,48
intestinal secretion and absorption and survival time of
animals.
49
One experiment in wild mice found no effect of chronic
helminth infection on either primary or memory T regulatory cell
response, progression to Mycobacterium tuberculosis infection and
BCG efficacy.
50
Data on other vaccines showed harmonious results with evidence
of impaired antibody or cytokine responses among helminth infected
compared to uninfected animals for tetanus,
51,52
diphtheria,
53
influenza,
8,54
hepatitis B,
11,55
pertussis,
56
pneumococcal,
57
HPV,
12
yellow fever,
58
cholera
59
and rabies
60
vaccines. The stage of parasite
infection seemed to play a role in whether a difference was found, for
instance in two studies on hepatitis B and tetanus, there was no sig-
nificant difference in vaccine responses between the groups when Tri-
chinella spiralis infection was in muscle stage
55
or when vaccination
was done in the prepatent period (1–6 weeks after Schistosoma man-
soni infection).
52
3.3 |Quality assessment
Risk of bias assessment for human studies showed there was signifi-
cant underreporting or lack of blinding of outcome assessors. Among
the included articles, only 16% reported blinding for both participants
and outcome assessors. Taking into consideration all eight risk of bias
components, 18 (49%) articles had a moderate or strong rating
(Appendix 2 in Supporting Information). For animal studies, studies
frequently did not report whether there was allocation concealment,
blinding of outcome assessors, random allocation of animals to inter-
vention arms, or whether animals were housed randomly during the
experiment. For each of these components, more than 80% of studies
had a high or unclear risk of bias (Appendix 3 in Supporting Informa-
tion). Funnel plots and Egger's test indicated the presence of publica-
tion bias (Appendix 8 in Supporting Information for direct helminth
exposure studies and Appendix 9 in Supporting Information for prena-
tal helminth exposure studies). A sensitivity analysis excluding one
extremely large effect size each from direct helminth exposure
61
and
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from prenatal helminth exposure risk of bias analyses
62
changed
Egger's test pvalues from .001 to .523 for direct helminth exposure
and from <.001 to .101 for prenatal helminth exposure.
4|DISCUSSION
We have presented results of a narrative summary and meta-analysis
on the effect of helminths on vaccine responses for human studies
and a narrative summary of findings for animal studies. Results from
the meta-analysis show that, when data on all vaccines were com-
bined, established helminth infection at the time of vaccination affects
vaccine-specific immune responses. These findings are consistent
with another review that investigated the effect of ‘parasitic’infec-
tions on vaccines.
16
However, the patterns and mechanisms involved
are complex and differ depending on the type of vaccine, the helminth
species and whether it is direct helminth infection/treatment or pre-
natal infection/treatment that is being assessed. The results show that
direct helminth exposure reduced responses to BCG and measles vac-
cines, both of which are live vaccines, although only one article was
identified for measles. It has been shown that live vaccines may be
more likely to be negatively affected by presence of helminths
4
and
this may explain the results we observed. Hepatitis B, a non-live vac-
cine was also negatively affected as shown from two studies. When
data from all vaccines were combined, we did not find evidence that
prenatal helminth exposure/treatment significantly affected responses
to vaccines overall, although meta-analysis results for pertussis
showed an adverse association with maternal helminth infection,
whilst a meta-analysis for live, oral polio vaccine (and one study on
live, oral rotavirus vaccine) showed higher vaccine responses among
infants of infected mothers. Because of a small number of articles per
vaccine, vaccine specific results should be interpreted with caution.
Results from animal studies showed that helminth infection at the
time of vaccination reduced responses to BCG. Although we found
few studies for other vaccines (tetanus, diphtheria, influenza,
hepatitis B, pertussis, pneumococcal, HPV, yellow fever and cholera),
results from these studies reported impaired vaccine specific
responses due to helminth infection. Results from animal experiments
were more consistent than for humans. A possible explanation for this
is that in mice, the helminth infection is controlled in terms of dose
and timing, intensity of infection may be greater than in otherwise
healthy human subjects, and (except in wild mice) issues of confound-
ing with other environmental exposures and factors such as nutrition
are avoided.
The negative effect of helminths on BCG responses was consis-
tent for studies of direct helminth exposure. The findings observed
from human studies are supported by earlier experiments in mice that
showed reduced purified protein derivative (PPD)-specific in-vitro
interferon gamma,
41–43
lymph node expansion
46
and delayed hyper-
sensitivity in footpad swelling
47
among helminth-infected mice. In one
experiment where mice were challenged with tubercle bacilli after
immunization, helminth-infected mice died earlier than uninfected
mice.
49
Studies that investigated the effect of prenatal helminth
exposure generally found no associations with BCG-specific immune
responses. These findings emphasize the importance of giving BCG at
birth and have implications for the use of BCG ‘booster’vaccination.
When we looked at studies investigating the effect of direct hel-
minth exposure on Hepatitis B responses, we found that infection
before vaccination significantly impaired responses to Hepatitis
B. This was based on data from only two studies and there was sub-
stantial heterogeneity among SMDs, although all estimates showed
the same direction of effect. We did not find evidence of an effect of
prenatal helminth exposure on responses to Hepatitis B vaccine.
In our analysis, most vaccines were not significantly affected by
prenatal helminth infection/treatment, however we found that for
pertussis there was some evidence from meta-analysis of two studies
that vaccine responses were reduced among infants of infected/
untreated mothers. On the other hand, based on results from two
studies, vaccine specific responses to live, oral polio were higher
among infants of helminth infected/untreated compared to unin-
fected/treated mothers and, interestingly, the one study on live, oral
rotavirus vaccine in infants showed a similar effect.
The findings from studies on tetanus toxoid and direct helminth
exposure showed conflicting results, however the results indicated that
on average TT vaccine responses were not significantly affected by hel-
minth infection. A sensitivity analysis excluding one study with very
small sample size and a large effect size did not alter this conclusion.
However, an animal experiment involving a Swiss mouse found that
prolonged infection with Schistosoma mansoni before vaccination
resulted in lower antitoxin titres.
52
This accords with evidence that
chronic helminth infection alters vaccine responses more than acute
helminth infection.
16
Similarly, for human studies, overall we found no
evidence that prenatal exposure to helminths affected responses to TT.
For many vaccines included in the human study review, that is,
measles, influenza, meningococcal, oral typhoid, polio and cholera we
found either only one article or could not obtain data suitable for a
meta-analysis. This emphasizes that there are research gaps relating
to many common vaccines. The findings from the individual studies
reported differing results with some studies reporting significant
reduction in responses due to helminth infection
35,63
and others no
effect.
39,64
Results from single studies should be interpreted with cau-
tion as they may not be generalizable.
In our meta-analysis, we found large heterogeneity between stud-
ies for some vaccine types and we could not interrogate this further
using meta regression due to the small number of studies. However,
heterogeneity was low to moderate for BCG for direct helminth expo-
sure studies and for tetanus, diphtheria, Hepatitis B, pertussis and
polio for prenatal helminths exposure studies. Despite large heteroge-
neity between studies for some vaccines, these findings are still rele-
vant as they show the average effect of helminths on vaccine
responses and also highlight the diverse situations in which studies on
this topic are designed and conducted. Differences in geographical
locations, varying follow-up periods, timing of measurement of
responses after vaccination, choice of outcome measure to assess,
length of period between anthelminthic treatment and vaccination,
method of helminth diagnosis, type of helminth and location of
NATUKUNDA ET AL.7of10
helminth in the body (i.e., blood, tissue, or gut), all of which vary from
study to study, may all contribute to explain this variability. In our
analysis, we acknowledge the presence of the unexplained heteroge-
neity between the studies and used a random effects model that takes
this into account whilst estimating the average effect. Also, in the
meta-analysis, we included responses to vaccines that are thought to
be the best correlates of protection. However, we have noted several
studies where responses other than antibody responses were signifi-
cantly affected by presence of helminth infection. This may have an
impact on the overall interpretation of our results. Also, for some hel-
minth ‘mass treatment’studies (where participants were randomized
regardless of baseline infection status), the prevalence of helminths at
baseline was low which potentially underestimated the effect of
anthelminthic treatment on vaccine responses. Furthermore, different
helminths may affect vaccine responses differently; however, it was
not possible to investigate this since most studies reported infection
with multiple helminths. A large percentage of studies included in our
review and meta-analysis did not report on blinding of outcome asses-
sors during the conduct of the studies which left unanswered the
question of whether there was no blinding at all or if it was simply not
reported. It is possible that articles published in languages other than
English could have been missed even when the literature search was
not restricted to articles published in English. This review did not look
at studies where helminth infection is determined after vaccination
and how this might affect already established immune responses, this
is a question that remains to be addressed in future reviews. We
acknowledge that co-infections with other parasites may confound
the relationship between helminths and vaccine responses, however
we did not investigate this further due to limited data reported on
such infections. Lastly, we did not include investigational vaccines
because assessment of helminth infection is seldom included in trial
protocols even in endemic settings, and furthermore, early phase vac-
cine trials often include a different age group (with different helminth
exposure) to the eventual target age group for the vaccine. Results of
this review suggest that assessment for helminths should be consid-
ered, especially for vaccines that will be used, and often most needed,
in helminth-endemic settings.
5|CONCLUSION
Overall, we found that helminths interfere with some vaccine
responses, with more consistent results from animal studies than from
studies in humans. Further, it is clear that the effect of helminths on
some vaccines such as BCG and Tetanus Toxoid has been investigated
more than other vaccines. For the less investigated vaccines, little is
known about the impact of helminths on response to these vaccines.
With this review and meta-analysis, we have presented evidence that
established helminth infection at the time of vaccination impairs
responses to BCG and Hepatitis B vaccines in humans and several
vaccines are affected in animals. Furthermore, in humans, these
effects are predominantly seen among individuals directly exposed to
helminths rather than helminth exposure in utero. The findings
presented here suggest that treatment of direct helminth infection
before vaccination may help improve responses. However, stronger
trials are needed to inform government policy regarding the need for
treatment of worms before immunization. Consideration of helminths
and other co-infections in early-phase trials of new vaccines intended
for helminth-endemic settings may be beneficial.
AUTHOR CONTRIBUTIONS
Alison M. Elliott conceived the idea. Agnes Natukunda conducted the
literature searches, Agnes Natukunda, Ludoviko Zirimenya, Gyaviira
Nkurunungi, Jacent Nassuuna screened articles for relevance and con-
ducted the subsequent data extraction, Emily L. Webb was the third
reviewer in case of disagreement between the two reviewers each for
human and animal studies, respectively. Agnes Natukunda conducted
data analysis, Agnes Natukunda, Emily L. Webb and Alison M. Elliott
contributed to data interpretation, Agnes Natukunda drafted the man-
uscript. All authors reviewed, provided input and approved the final
version of the manuscript.
ACKNOWLEDGEMENTS
We are grateful to authors of published articles (Indu Malhotra and
Noah D. McKittrick) who provided additional data for inclusion in the
meta-analysis. The work was conducted at the MRC/UVRI and
LSHTM Uganda Research Unit which is jointly funded by the UK
Medical Research Council (MRC) part of UK Research and Innovation
(UKRI) and the UK Foreign, Commonwealth and Development Office
(FCDO) under the MRC/FCDO Concordat agreement and is also part
of the EDCTP2 programme supported by the European Union.
FUNDING INFORMATION
Medical Research Council of the United Kingdom, Grant Number:
MR/R02118X/1.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1111/pim.12939.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ORCID
Agnes Natukunda https://orcid.org/0000-0003-1156-201X
Gyaviira Nkurunungi https://orcid.org/0000-0003-4062-9105
Stephen Cose https://orcid.org/0000-0002-5156-037X
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SUPPORTING INFORMATION
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How to cite this article: Natukunda A, Zirimenya L,
Nassuuna J, et al. The effect of helminth infection on vaccine
responses in humans and animal models: A systematic review
and meta-analysis. Parasite Immunol. 2022;e12939. doi:10.
1111/pim.12939
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