Should the Human Microbiome Be Considered When Developing Vaccines?


article has not abstract


Published in the journal: . PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001190
Category: Opinion
doi: https://doi.org/10.1371/journal.ppat.1001190

Summary

article has not abstract

The human microbiome, especially in the intestinal tract has received increased attention in the past few years due to its importance in numerous biological processes. Recent advances in DNA sequencing technology and analysis now allow us to better determine global differences in the composition of the gut microbial population, and ask questions about its role in health and disease. Thus far, roles of these commensal bacteria on nutrient acquisition, vitamin production, and intestinal development have been identified [1]. Furthermore, resistance or susceptibility to a number of diseases, including inflammatory bowel disease, obesity, enteric infections, and most recently ectopic diseases, have been linked to the intestinal microbiota [1], [2]. Data on the mechanisms through which the intestinal microbiota impacts host immune development have also begun to emerge [2]. The impact of the intestinal microbiota on host physiology is undeniable, and experiments using germ-free, mono-, and poly-colonized mice have addressed many aspects of the microbiota's influence on the mammalian immune system.

Despite all the increased attention on the interface between the microbiota and host immune responses, it is still unclear whether these commensal bacteria affect the efficacy of vaccines. Due to its impact in the development of immune function, both in the gut and other organs, it is reasonable to consider that the intestinal microbiota will significantly affect how individuals respond to vaccine antigens [3], [4]. For example, segmented filamentous bacteria present in the intestinal microbiota have been shown to induce maturation of intestinal T cell adaptive functions [5]. Moreover, it has been shown that the intestinal microbiota exerts a profound effect on the metabolism of certain drugs and toxins [1], [6], and this may also indicate that oral vaccines could be differentially processed by the body depending on variations in microbial communities between individuals. Hence, the microbiota could be an underappreciated yet important player to consider in the development of vaccines, and also may help explain some of the discrepancies observed in vaccine efficacy in different populations around the world.

Clinical trials testing the efficacy of oral vaccines against polio, rotavirus, and cholera have showed a lower immunogenicity of these vaccines in individuals from developing countries when compared to individuals from the developed world [7][11]. Clinical trials for a killed oral cholera vaccine in Swedish and Nicaraguan children have also shown blunted antibody responses in Nicaraguan children compared to Swedish children [11]. In a study testing a live cholera oral vaccine, Lagos and colleagues [12] demonstrated that excessive bacterial growth in the small intestine of children in less developed countries might contribute to the low antibody response to the vaccine. Different vaccine strains of Shigella flexneri also showed differential protection on individuals from developing countries. In a study testing Bangladeshi adults and children, no significant immune response to this vaccine was mounted, although the same antigen was reactogenic in North American individuals [13]. Altogether, these data highlight that individuals from different parts of the world can mount different immune responses to the same vaccine. Several hypotheses that may explain this phenomenon exist. For instance, socioeconomic conditions, nutritional status, host genetics, and earlier exposure to related microorganisms are some of the aspects that could contribute to the disparity in the vaccine efficacies in different populations. However, one poorly explored possibility is that the composition of the intestinal microbiota of these individuals may also be a determining factor of vaccine efficacy. In a way analogous to the hygiene hypothesis [14], which states that reduced exposure to microorganisms at an early age may lead to increased susceptibility to allergies, it is possible that the gut microbiota of individuals with increased exposure to microorganisms (and therefore antigens) make them more tolerant to vaccination, being unable to mount a proper response compared to individuals living in better socioeconomic conditions.

Discerning the effects of genetic and environmental factors on vaccine efficacy is a challenging task. Large clinical trials involving individuals from different areas of the world will likely be required to shed light on whether the blunt immune responses to some of the oral vaccines mentioned herein are a consequence of genetic factors or environmental variations, such as the gut microbial community. Studies involving immigrant volunteers could be useful in addressing this issue by providing a clear distinction between the effects of genetics and the environment. Although this is still an open question, data in the literature suggest a more direct link between the intestinal microbiota composition and the development of immune responses to certain vaccine antigens. For instance, the use of antibiotics in chickens has been shown to increase the antibody response following immunization [15]. Because antibiotic treatment will have profound effects on the intestinal microbiota, it is tempting to hypothesize that the microbial populations of these animals are important players in their immunological response to the vaccine antigens. Furthermore, certain probiotic strains have been shown to enhance antibody responses to oral vaccines against rotavirus [16], Salmonella [17], polio [18], and cholera [19] in human volunteers, and this effect was observed after a short period (1–5 weeks) of probiotic treatment. The positive effect of probiotics on immune responses was also seen in parenterally administered vaccines against diphtheria, tetanus, Haemophilus influenzae type B, and hepatitis B [20][22] in infants after a 6-month period. Because of the number of licensed oral-administered human vaccines available is limited, studies on how the intestinal microbiota affect parenterally administered human vaccines would have a more significant impact on human health. However, in all studies cited above, there was no long-term follow-up on the enhanced effects of the probiotics on vaccine efficacy. Additionally, more detailed studies on the establishment of the probiotic strains within the resident microbiota will be required to establish minimal doses and treatment regimens, important aspects that need to be addressed if the microbiota is to be considered in vaccine development in the future. It has also been suggested that prebiotics, which are compounds that can enhance the proliferation of certain commensals, can enhance the efficacy of oral vaccines. Recently, a well-studied fructo-oligosaccharide prebiotic has been shown to improve the efficacy of a vaccine against Salmonella infection [23]. In this study, administration of the prebiotic prior to vaccination improved host responses and rates of protection against infection in mice. Unfortunately, the authors were unable to show significant changes in microbiota composition, possibly due to the lack of detailed analyses. In another study, Vos et al. [24] showed that a prebiotic mixture containing galacto- and fructo-oligosaccharides enhanced systemic adaptive immune responses in a murine influenza vaccination model. In this case, increased proportions of certain members of the microbiota could be observed, suggesting a role for the microbial community in the increased host immune response.

Although some studies indicate that the microbiota may play an important role in vaccine efficacy, this area of research is still in its infancy. For instance, the mechanisms involved in the pro- and prebiotic enhancement of vaccine efficacy mentioned above are largely unknown. Nevertheless, current knowledge of the effect of the intestinal microbiota on the development of not only local but also systemic immune functions provides a direct link between commensal populations in the intestine and immune responses to vaccine antigens [3], [4]. We now have the tools to study and take advantage of what the microbiota has to offer in order to enhance host responses to vaccines, with the use of probiotics or prebiotics as adjuvants. Studies using animal models with defined intestinal microbial communities can be helpful to evaluate the effect of intestinal commensals on the immune response to vaccines. However, animal models can only partially elucidate this issue and, although cumbersome, studies in human volunteers will be essential in defining the effect of commensals in vaccine efficacy. We suggest that the study of the relationships between individual commensal populations of humans and responses to vaccines will be instrumental in our quest to improve general vaccine development. By taking into consideration the microbial populations of geographically diverse groups of individuals, we may be able to develop better-targeted vaccines that will improve protection against multiple pathogens.


Zdroje

1. SekirovI

RussellSL

AntunesLCM

FinlayBB

2010

Gut microbiota in health and disease.

Physiol Rev

90

859

904

2. AbtMC

ArtisD

2009

The intestinal microbiota in health and disease: the influence of microbial products on immune cell homeostasis.

Curr Opin Gastroenterol

25

496

502

3. UmesakiY

SetoyamaH

2000

Structure of the intestinal flora responsible for development of the gut immune system in a rodent model.

Microbes Infect

2

1343

1351

4. BosNA

MeeuwsenCG

WostmannBS

PleasantsJR

BennerR

1988

The influence of exogenous antigenic stimulation on the specificity repertoire of background immunoglobulin-secreting cells of different isotypes.

Cell Immunol

112

371

380

5. Gaboriau-RouthiauV

RakotobeS

LecuyerE

MulderI

LanA

2009

The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses.

Immunity

31

677

689

6. WilsonID

NicholsonJK

2009

The role of gut microbiota in drug response.

Curr Pharm Des

15

1519

1523

7. JohnTJ

1993

Experience with poliovaccines in the control of poliomyelitis in India.

Public Health Rev

21

83

90

8. PatriarcaPA

WrightPF

JohnTJ

1991

Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries: review.

Rev Infect Dis

13

926

939

9. HanlonP

HanlonL

MarshV

ByassP

ShentonF

1987

Trial of an attenuated bovine rotavirus vaccine (RIT 4237) in Gambian infants.

Lancet

1

1342

1345

10. Suharyono

SimanjuntakC

WithamN

PunjabiN

HeppnerDG

1992

Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5-9-year-old Indonesian children.

Lancet

340

689

694

11. HallanderHO

PaniaguaM

EspinozaF

AskelofP

CorralesE

2002

Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children.

Vaccine

21

138

145

12. LagosR

FasanoA

WassermanSS

PradoV

San MartinO

1999

Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR.

J Infect Dis

180

1709

1712

13. WHO

2006

Future needs and directions for Shigella vaccines.

Wkly Epidemiol Rec

81

51

58

14. StrachanDP

1989

Hay fever, hygiene, and household size.

BMJ

299

1259

1260

15. BrisbinJT

GongJ

LustyCA

SabourP

SaneiB

2008

Influence of in-feed virginiamycin on the systemic and mucosal antibody response of chickens.

Poult Sci

87

1995

1999

16. IsolauriE

JoensuuJ

SuomalainenH

LuomalaM

VesikariT

1995

Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG.

Vaccine

13

310

312

17. FangH

ElinaT

HeikkiA

SeppoS

2000

Modulation of humoral immune response through probiotic intake.

FEMS Immunol Med Microbiol

29

47

52

18. de VreseM

RautenbergP

LaueC

KoopmansM

HerremansT

2005

Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination.

Eur J Nutr

44

406

413

19. PaineauD

CarcanoD

LeyerG

DarquyS

AlyanakianMA

2008

Effects of seven potential probiotic strains on specific immune responses in healthy adults: a double-blind, randomized, controlled trial.

FEMS Immunol Med Microbiol

53

107

113

20. WestCE

GotheforsL

GranstromM

KayhtyH

HammarstromML

2008

Effects of feeding probiotics during weaning on infections and antibody responses to diphtheria, tetanus and Hib vaccines.

Pediatr Allergy Immunol

19

53

60

21. KukkonenK

NieminenT

PoussaT

SavilahtiE

KuitunenM

2006

Effect of probiotics on vaccine antibody responses in infancy—a randomized placebo-controlled double-blind trial.

Pediatr Allergy Immunol

17

416

421

22. SohSE

OngDQ

GerezI

ZhangX

ChollateP

2010

Effect of probiotic supplementation in the first 6 months of life on specific antibody responses to infant Hepatitis B vaccination.

Vaccine

28

2577

2579

23. BenyacoubJ

RochatF

SaudanKY

RochatI

AntilleN

2008

Feeding a diet containing a fructooligosaccharide mix can enhance Salmonella vaccine efficacy in mice.

J Nutr

138

123

129

24. VosAP

HaarmanM

BucoA

GoversM

KnolJ

2006

A specific prebiotic oligosaccharide mixture stimulates delayed-type hypersensitivity in a murine influenza vaccination model.

Int Immunopharmacol

6

1277

1286

Štítky
Hygiena a epidemiologie Infekční lékařství Laboratoř

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