Influence of the microbiome on response to vaccination

Abstract

In order for vaccines to be effective within a given population not only do large numbers of people need to be vaccinated, but a large proportion of those vaccinated must develop protective immunity. The mechanisms that lead to a poor immune response to vaccination are complex and poorly understood, but include both genetic and environmental factors. The bacteria that exist throughout the human body, known as the microbiome, play a variety of roles in the development of the immune system. This is particularly true during infancy when the microbiome and the immune response are developing in tandem. Most vaccines are administered in early childhood to prevent outbreaks of devastating childhood diseases. Understanding the impact that the early microbiome plays in response to vaccination will improve our understanding of vaccine efficacy.

Keywords:

• vaccinations
• microbiome
• virome
• mycobiome
• vaccine
• protective immunity

Mechanisms of Vaccine Non-Responders

The effectiveness of any vaccination strategy depends on the percentage of people in any population that develop protective immunity. This is referred to as “herd immunity,” and prevents disease outbreaks. The number of vaccinated people within a population that is necessary to prevent spread of infections depends on a variety of factors including the transmissibility of the infection and the effectiveness of the vaccine. If within the vaccinated population a large proportion of subjects do not produce an effective response (referred to as non-responders) the percentage of vaccination coverage will need to be higher to provide population-wide protection. Therefore an improved understanding of mechanisms leading to defective responses to vaccines is needed to decrease outbreaks of infectious diseases. The mechanisms behind a lack of response to a given vaccine are complex. There are a number of potential reasons why an individual does not respond to vaccines including both genetic and environmental factors.^1-5 The clearest genetic link is between specific HLA haplotypes and a lack of response to certain vaccines.⁶ In addition vaccine non-responders may encompass an entire family. When this occurs in extended families pockets of infectious disease susceptibility can emerge. In addition environmental effects and physical parameters appear to play a role in response to vaccination. These include an older age, gender, and smoking.⁷ Many factors that affect the health-status of an individual will also affect the response to vaccination. For example immunosuppressive chemotherapy treatment for diseases such as cancer, as well as chronic infections that cause immunosuppression will lead to decreased efficacy of vaccinations.^5,8-10 Celiac disease patients have decreased seroconversion to the hepatitis B vaccine, which may be linked to genetic components, environmental components, or both.³ It has been shown that chronic infection with many viruses including human cytomegalovirus (CMV) and human human immunodeficiency virus (HIV) infection decreases the effectiveness of many vaccines.^5,10 Not only do pathogens exert immunomodulatory effects, but the microbes that populate a healthy human host, known as the microbiome, can also influence the immune response.^4,11 What role changes in the microbiota during disease states play in response to vaccines is an important subject for study in order to understand the response to vaccines. In addition the variance in microbiomes between individuals may be an important environmental factor that influences vaccine efficacy.

Microbiome and the Immune Response

The human body has more microbial cells than human cells. These microbes are collectively known as the microbiome.^12-16 While the majority of these microbiota exist in the intestinal tract, there are microbes in other areas including the skin, airway, and genital tract.^17-19 In addition there is an extensive virome and mycobiome that are less well characterized, but likely play important roles in many aspects of human health.^20,21 Considerable research in recent years has revealed that the intestinal microbiome influences a wide variety of functions include the development of the immune system and regulation of the immune response. For example, germ-free mice or mice treated with antibiotics have defects in the immune response to infectious diseases. The innate immune response to influenza A virus was severely compromised in mice that had been depleted of bacteria by antibiotic treatment. When these mice had their microbiome restored, or their innate immune system stimulated their immune response recovered.²² In addition the composition of the microbiome affects aspects of the adaptive immune system that are crucial to response to vaccines. This includes antibody diversification and B cell and T cell development.^11,23 The type of helper or regulatory T cell response is connected to changes in the microbiome.²³ Immediately after birth a baby begins to be populated with bacteria. This process is dynamic over the initial 6 months of life, but the microbiome becomes largely stable after this. Even if the microbiome is disrupted transiently it will repopulate itself largely as it was initially established.^14,24 The immune response and the mcirobiome develop in concert during these first few months. As many vaccinations are given early in life, the composition of this early microbiome potentially plays an important role in the response to vaccines.

New Potential Areas of Research

In order to understand what is clearly an important environmental factor in vaccine efficacy, we must explore the impact of the microbiome on the immune response to vaccines. Proposals for using a systems biology approach to investigate the diverse responses to vaccination include analysis of the microbiome as a factor in the response.⁶ There is a clear potential intersection of intestinal microbiome research and vaccine responses with oral vaccines. The effect of intestinal infections on the efficacy of the oral polio vaccine has been investigated, but the impact of the intestinal microbiome on vaccine efficacy is not well studied. In addition, since changes in the microbiome impact many aspects of the immune response the efficacy of systemic vaccines will also be affected by microbiome changes. Using germ-free or antibiotic treated animal models the impact of microbiome changes on vaccination can be studied. This could also be examined by correlating serocoversion rates with childhood antibiotic use. This research will enable us to direct the timing of vaccine administration, and avoid proximity to antibiotic administration if necessary. In addition new vaccine technology includes respiratory vaccines (nasal mist), and intradermal vaccines. These new areas of vaccination will require a deeper understanding of the microbes that make up these areas. Extra-intestinal microbiomes, such as the airway and the skin are relatively new areas of interest. Very little is known about the impact of these microbiomes on the development of the immune system and response to infections. Increased understanding of the interaction of these location-specific microbiomes with cells of the immune system will expand our understanding of the immune response to vaccination. Most vaccines are given in early childhood while both the microbiome and the immune system are developing. Careful attention should be given to understanding how the early microbiome affects vaccination, and how vaccination may influence the development of the early microbiome.

Achieving an effective response to a vaccine is complex process that includes many variables. The microbiome has been demonstrated to play many roles in the development of the immune system, and in the response to infectious diseases. The effects of the microbiota on the ability to respond to specific vaccinations, and if altering the microbiota can improve vaccine efficacy are 2 important areas of vaccine research.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.