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COVID-19 Vaccination Programs And Implications Of The Human Microbiome

It is vital to understand the role of the microbiome in immunity and vaccine response, and how the microbiome may impact the effectiveness of COVID-19 vaccine programs in the real world.

The world is depending on the success of vaccine programs to end the ongoing COVID-19 pandemic. To curb the spread of the virus, it is essential for a population to reach herd immunity, where a significant proportion has developed immunity to infection. There are currently 11 vaccines authorized/approved for use in multiple countries worldwide. According to clinical trial data, these vaccines have demonstrated relatively high efficacy in preventing COVID-19 infection. However, this does not mean that the vaccines will be as effective in the real world. Vaccine response can vary at an individual level and can be influenced by a multitude of biological factors, including the function of the microbiome. 
The microbiome plays a significant role in immunity, and may be an underlying factor explaining why elderly people and those with certain comorbidities are at higher risk of infection. The underlying impact of microbiome dysbiosis on immunity may not only increase instances of severe disease in high-risk groups but may also affect their response to the COVID-19 vaccines. Therefore, it is vital to understand the role of the microbiome in immunity and vaccine response, and how it may impact the effectiveness of vaccine programs in the real world. 

The COVID-19 Vaccination Program

Since the pandemic began, multiple vaccines with varying mechanisms of action and technology have been developed, approved and distributed at unprecedented speed. According to Citeline’s Pharmaprojects, there are 11 (as of 12 April 2021) vaccines approved or given emergency use authorization in various countries across the globe (see Exhibit 1).

Exhibit 1.

Vaccines With Authorization/Approval For Use

Vaccine details

Originator company

Authorization/Approval countries

COVAXIN

Inactivated COVID19 vaccine

Bharat Biotech, India

Mexico, Zimbabwe, India

Convidecia

Recombinant adenovirus vaccine

CanSino Biologics, China

China, Mexico, Hungary, Pakistan

CoronaVac

Inactivated Covid-19 vaccine

Sinovac Biotech, China

China, Seychelles, Indonesia, Turkey, Brazil, Pakistan, Chile, Morocco, Philippines, Peru, Hungary, Mexico, Hong Kong, Thailand, Venezuela, Malaysia, Ecuador, Ukraine, Zimbabwe

ChAdOx1

Recombinant adenovirus vaccine

Oxford Biomedica & AstraZeneca, United Kingdom

United Kingdom, Mexico, Bangladesh, Argentina, India, Nepal, Pakistan, Brazil, Thailand, Myanmar, Ecuador, Bahrain, Philippines, South Africa, Chile, the EU, Vietnam, United Arab Emirates, Norway, South Korea, Australia, Taiwan, Ukraine, Afghanistan, Colombia, Canada, Moldova, Indonesia, Portugal, Iraq, Costa Rica

mRNA-1273

mRNA-based vaccine

Moderna, United States

United States, Canada, Israel, the EU, Switzerland, Singapore, Qatar, Hungary, Vietnam, United Kingdom

2019-nCoV vaccine

Recombinant adenovirus vaccine

Janssen (Johnson & Johnson), Belgium

South Africa, Bahrain, United States, Canada, France, Switzerland, Thailand, Colombia, Brazil, South Korea, Tunisia, Jordan, Qatar, Saudi Arabia

Sputnik V

Recombinant adenovirus vaccine

The Gamaleya Research Institute, Russia

Russia, Argentina, Bolivia, Algeria, Venezuela, Mexico, Paraguay, Turkmenistan, Hungary, United Arab Emirates, Iran, Philippines, Armenia, Tunisia, Nicaragua, Lebanon, Pakistan, Mongolia, Iran, Egypt, Hungary, Vietnam, Slovakia, Laos, Sri Lanka, Zimbabwe, Czech Republic, Mali

COVIV

Inactivated COVID-19 vaccine

Wuhan Institute of Biological Products (China National Biotec Group), China

China, Bahrain

BNT-162

mRNA-based vaccine

 

BioNTech & Pfizer, Germany

United States, United Kingdom, Bahrain, Canada, Mexico, Singapore, Saudi Arabia, United Arab Emirates, Chile, Switzerland, Israel, the EU, Colombia, Philippines, Australia, Hong Kong, Peru, South Korea, New Zealand, India, Canada, Japan, Brazil, Rwanda

BBIBP-CorV

Inactivated COVID-19 vaccine

Beijing Institute of Biological Products

United Arab Emirates, Bahrain, China, Serbia, Pakistan, Peru, Laos, Iraq, Hungary, Zimbabwe, Nepal, Argentina, Senegal, Hungary, Argentina

ZF-2001

Recombinant CHO cell vaccine

Anhui Zhifei Longcom Biopharma, China

China, Uzbekistan

Source: Pharmaprojects, April 2021

The first vaccines were only approved at the end of 2020 and global demand still far outstrips supply. Considering this scarcity, the initial aim of many countries’ vaccination programs is to ensure that those who are most at risk of severe disease or death are prioritized. An Informa Pharma Intelligence analysis estimates that the global population of people falling into the top priority groups for vaccination (healthcare workers and people aged over 65 years) is approximately 787.5 million, and considering that most vaccinations require two doses, around 1.8 billion doses are needed to cover this group alone. As well as the top priority groups, those with various comorbidities (including obesity, diabetes, chronic lung or heart disease) are also at higher risk of severe disease and death from COVID-19 and placed high on the vaccine priority list.

Due to inequity of vaccine distribution across the globe, some countries have been able to move into vaccinating non-priority populations, while others are yet to even start vaccinating. According to the World Health Organization, 700 million vaccine doses have been administered globally, but over 87% of these have gone to high- or upper-middle-income countries while just 0.2% have gone to low-income countries. Accordingly, the top five countries with the highest share of people receiving at least one vaccine dose are all high- and upper-middle-income (see Exhibit 2).

Exhibit 2.

Top Five Countries With Highest Share Of Population Receiving COVID-19 Vaccine

Country

% population receiving single vaccine dose

% population fully vaccinated

Israel

61.5%

57.0%

United Kingdom

47.3%

11.0%

United States

35.7%

21.7%

Bahrain

33.2%

23.0%

Hungary

30.0%

12.6%

Source: Our World In Data, 2021   [Note: Correct as of 11 April 2021]

The overarching aim of mass vaccination programs is to achieve herd immunity in the population. Herd immunity is reached when a significant proportion of people in the population have immunity to a disease, either through prior infection and recovery, or vaccination, which thus means that there is a natural resistance to disease spread. For COVID-19, it is estimated that the threshold for herd immunity is when 60­­–70% of the population are immune. Countries with high levels of vaccination are hoping to reach this threshold soon, but the majority of the current vaccine pipeline (all apart from Johnson & Johnson/Janssen’s vaccine) require two doses in order to influence an immune response. So, although the above single-dose figures look promising for the countries included in Exhibit 2, there is still a way to go to for the vaccine programs and the speed at which they are rolled out is dependent on the logistics of supply, distribution and uptake.

Along with these logistical factors, the success of vaccine programs also depends on the efficacy of the vaccine distributed in preventing infection and illness. Much of what we understand about the efficacy of the vaccines is based on data from clinical trials. Multiple authorized/approved vaccines are one of three main types: inactivated virus, recombinant adenovirus vectors, or mRNA-based. Based on clinical trial data, they all have varying levels of efficacy in preventing illness from COVID-19. Overall, it seems that efficacy ranges are highest in mRNA-based vaccines compared to other types (see Exhibit 3).

Exhibit 3.

Efficacy Ranges For Three Main Types Of Vaccine Based On Phase III Data

Vaccine type

Vaccine & developer

(ordered by least to most efficacious)

Range of efficacy estimates based on Phase III trials

Inactivated virus

COVAXIN, Bharat Biotech

81.0% – 86.0%

CoronaVac, Sinovac Biotech

COVIV, Wuhan Institute of Biological Products (China National Biotec Group)

BBIBP-CorV, Beijing Institute of Biological Products

Recombinant adenovirus vector

Convidecia, CanSino Biologics

65.7% – 91.6%

ChAdOx1, Oxford Biomedica & AstraZeneca

2019-nCoV vaccine, Janssen

Sputnik V, The Gamaleya Research Institute

mRNA-based

mRNA-1273, Moderna

94.1% – 95.3%

BNT-162, BioNTech & Pfizer

 

Source: Trialtrove, April 2021

It is important to note that these data are based on clinical trials ran in exclusive populations, and therefore, results may not be the same in the real world. The efficacy levels quoted above are estimated by comparing the number of infections resulting in a vaccinated group compared to an un-vaccinated placebo group. But, in fact, the actual ability of a vaccine to induce an immune response in an individual is dependent on a wide range of biological, lifestyle and environmental factors.

Interestingly, there is a growing body of literature which suggests that the human microbiome plays a major role in immunity and therefore risk of infection and response to vaccination, which may be an important factor to consider when understanding the effectiveness of COVID-19 vaccination programs in the real world.

The Role Of The Microbiome In COVID-19 Immunity

The microbiome is a complex system of symbiotic microbes (including bacteria, fungi, viruses, and other microbial species), which reside throughout the body, predominantly in the gut, and play a significant role in human physiology. In recent years, in-depth research of the microbiome and its function has demonstrated its role in maintaining health and causing disease. A functioning and health-inducing microbiome is very much dependent on a fine balance of specific microbiota populations. The microbiome may become imbalanced when there are too many ‘bad’ microbiota compared to ‘good,’ which results in dysbiosis. Dysbiosis is associated with a range of health conditions, including multiple autoimmune and inflammatory diseases, due to the microbiome’s role in immunity and inflammatory responses. When functioning well, the microbiome effectively plays a role in immune system development and gauges appropriate innate and adaptive immune responses in response to infection.

While COVID-19 is considered a respiratory disease, evidence suggests that often many patients also experience gastrointestinal (GI) symptoms when infected. Moreover, although the lungs and gut are not linked anatomically, they are physiologically linked and interact with the immune system through the microbiome’s gut-lung axis. Evidence suggests that gut microbiota play a role in the immune response against acute respiratory infections such as influenza. Also, viral GI symptoms cause inflammation and damage to the gut, which in turn affects the function of the microbiome, and therefore the effectiveness of the immune system. So, gut dysbiosis may affect COVID-19 outcomes and recovery. Indeed, a recent cohort study conducted across two hospitals demonstrated that gut microbiome composition was significantly altered in COVID-19 patients compared to uninfected individuals. Moreover, the study showed that severity of disease was proportionate to levels of immunomodulatory gut microbiota (including Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacterial), and patients with lower levels had more severe disease.

While SARS-CoV-2 has the ability to infect anyone, the WHO recommends prioritizing those most at risk of severe disease for vaccination, including those aged 65+ years or with various comorbidities (including diabetes, chronic respiratory disease, cardiovascular disease and obesity). Age is a major risk factor for severe disease and death in COVID. In the US, 80% of all recorded deaths from COVID-19 have been in adults aged over 65 years. The microbiome may be an important factor explaining why elderly people are so vulnerable to severe illness.

Aging is associated with significant changes in microbiome composition, and elderly people have a higher level of pro-inflammatory ‘bad’ microbiota than ‘good’ immunomodulatory microbiota. Dysbiosis is also evident in many people with various comorbidities, including those which increase risk for severe effects of COVID-19. Obesity is a particularly prevalent comorbidity for COVID-19 across the globe. According to an analysis of global pooled data on obese patients with COVID-19, risk of hospitalization and death is ~50% higher in infected obese patients compared to non-obese patients, and this is partially driven by reduced immune response to infections as a result of obesity. Microbiome dysbiosis is a feature of obesity as it influences dysregulation of nutrient metabolism and energy expenditure. The underlying impact dysbiosis has on immunity may explain why obese individuals are at a higher risk of COVID-19. Considering that dysbiosis is associated with many of the risk factors for severe COVID-19, when prioritizing people for vaccination, the health of the microbiome may be an important underlying mechanism to consider when assessing risk and potential efficacy of vaccination.

Future Implications

Considering the heavy involvement of the microbiome in immune response, it is not surprising that an abundance of evidence suggests it has the ability to influence response to vaccines also. The world is dependent on distribution of an effective vaccine to curb the ongoing COVID-19 pandemic, and trials have demonstrated relatively high efficacy for all approved/authorized vaccines. However, efficacy can vary greatly by individual, which results in varying population levels of protection seen at regional levels, as has been observed for many existing vaccines, such as the Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis and vaccines against poliomyelitis, rotavirus, malaria, and yellow fever. Multiple studies have demonstrated that there are correlations between the composition of microbiomes with varying levels of specific microbiota and response to vaccination, which may explain varying population-level protection in different regions. For example, responses to rotavirus vaccination in low- to middle-income settings have decreased effectiveness which is hypothesised to be influenced by microbiome composition. Accordingly, a clinical trial demonstrated that modification of the microbiome influences response to rotavirus vaccination.

Many of the risk factors for severe COVID-19 are associated with altered microbiota composition. The underlying impact of microbiome dysbiosis on immunity may not only increase risk of disease in people in these risk groups but may also affect their response to the COVID-19 vaccines. Elderly people in care homes have been hit particularly hard by the pandemic, and the vaccine is vital to prevent further outbreaks in such facilities. Immunosenescence is a feature of aging and frailty, which may blunt responsiveness to vaccines and could be driven by dysbiosis. Also, given the large prevalence of high-risk comorbidities in the general population which feature impaired immunity through dysbiosis, there is a risk that a vaccine may not actually be as effective in the real-world setting as it has been shown to be in trials. Moreover, researchers have suggested that vaccine adverse effects observed in high-risk patients, such as the 23 elderly people who died after receiving an mRNA-based vaccine in Sweden, may have been influenced by dysbiosis.

It is imperative that further research is conducted to assess vaccine effectiveness in high-risk individuals and better understand the role of the microbiome in influencing response. San Diego, US-based Persephone Biosciences this year initiated the VOICES (Vaccine Observation to Include all Communities for Equitable Science) study in order to find an answer to this important research question, and it is anticipated to complete in late 2022 according to Trialtrove. High-risk individuals may benefit from microbiome-modulating therapies to boost their immunity and improve their response to vaccines. If vaccine responsiveness is high for all individuals in a population, herd immunity may be achieved more effectively, and focusing on improving microbiome health may be the key to reaching this goal.

First published in IN VIVO, April 2021

 

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