A comprehensive perspective on the interaction between gut microbiota and COVID-19 vaccines

Figures & data

Table 1. A list of 50 COVID-19 vaccines that have been approved for use in 201 countries.

Vaccine Name	Manufacturer	Type of Vaccine	Approved Status	Number of Completed Clinical Trails	Granted EUL by WHO
Zifivax	Anhui Zhifei Longcom	Protein Subunit	Approved in 4 countries	21 trials in 5 countries	No
Noora vaccine	Bagheiat-allah University of Medical Sciences	Protein Subunit	Approved in 1 country	3 trials in 1 country	No
Corbevax	Biological E Limited	Protein Subunit	Approved in 2 countries	7 trials in 1 country	No
Abdala	Center for Genetic Engineering and Biotechnology (CIGB)	Protein Subunit	Approved in 6 countries	5 trials in 1 country	No
Soberana 02	Instituto Finlay de Vacunas Cuba	Protein Subunit	Approved in 4 countries	7 trials in 2 countries	No
Soberana Plus	Instituto Finlay de Vacunas Cuba	Protein Subunit	Approved in 2 countries	5 trials in 1 country	No
V-01	Livzon Mabpharm Inc	Protein Subunit	Approved in 1 country	7 trials in 3 countries	No
MVC-COV1901	Medigen	Protein Subunit	Approved in 4 countries	15 trials in 4 countries	No
Recombinant SARS-CoV-2 Vaccine (CHO Cell)	National Vaccine and Serum Institute	Protein Subunit	Approved in 1 country	3 trials in 2 countries	No
Nuvaxovid	Novavax	Protein Subunit	Approved in 40 countries	22 trials in 14 countries	Yes
IndoVac	PT Bio Farma	Protein Subunit	Approved in 1 country	4 trials in 1 country	No
Razi Cov Pars	Razi Vaccine and Serum Research Institute	Protein Subunit	Approved in 1 country	5 trials in 1 country	No
VidPrevtyn Beta	Sanofi/GSK	Protein Subunit	Approved in 30 countries	3 trials in 2 countries	No
COVOVAX (Novavax formulation)	Serum Institute of India	Protein Subunit	Approved in 6 countries	7 trials in 3 countries	Yes
SKYCovione	SK Bioscience Co Ltd	Protein Subunit	Approved in 1 country	7 trials in 6 countries	No
TAK-019 (Novavax formulation)	Takeda	Protein Subunit	Approved in 1 country	3 trials in 1 country	No
SpikoGen	Vaxine/CinnaGen Co.	Protein Subunit	Approved in 1 country	8 trials in 2 countries	No
Aurora-CoV	Vector State Research Center of Virology and Biotechnology	Protein Subunit	Approved in 1 country	4 trials in 1 country	No
Razi Cov Pars	Razi Vaccine and Serum Research Institute	Protein Subunit	Approved in 1 country	5 trials in 1 country	No
VidPrevtyn Beta	Sanofi/GSK	Protein Subunit	Approved in 30 countries	3 trials in 2 countries	No
COVOVAX (Novavax formulation)	Serum Institute of India	Protein Subunit	Approved in 6 countries	7 trials in 3 countries	No
SKYCovione	SK Bioscience Co Ltd	Protein Subunit	Approved in 1 country	7 trials in 6 countries	No
TAK-019 (Novavax formulation)	Takeda	Protein Subunit	Approved in 1 country	3 trials in 1 country	No
SpikoGen	Vaxine/CinnaGen Co.	Protein Subunit	Approved in 1 country	8 trials in 2 countries	No
Aurora-CoV	Vector State Research Center of Virology and Biotechnology	Protein Subunit	Approved in 1 country	2 trials in 1 country	No
EpiVacCorona	Vector State Research Center of Virology and Biotechnology	Protein Subunit	Approved in 4 countries	4 trials in 1 country	No
GEMCOVAC-19	Gennova Biopharmaceuticals Limited	RNA	Approved in 1 country	2 trials in 1 country	No
Covifenz	Medicago	RNA	Approved in 1 country	6 trials in 6 countries	No
Spikevax	Moderna	RNA	Approved in 88 countries	70 trials in 24 countries	Yes
Spikevax Bivalent Original/Omicron BA.1	Moderna	RNA	Approved in 38 countries	5 trials in 4 countries	No
Spikevax BivalentOriginal/Omicron BA.4/BA.5	Moderna	RNA	Approved in 33 countries	2 trials in 1 country	No
Comirnaty (BNT162b2)	Pfizer/BioNTech	RNA	Approved in 149 countries	100 trials in 31 countries	Yes
Comirnaty Bivalent Original/Omicron BA.1	Pfizer/BioNTech	RNA	Approved in 35 countries	3 trials in 5 countries	No
Comirnaty Bivalent Original/Omicron BA.4/BA.5	Pfizer/BioNTech	RNA	Approved in 33 countries	4 trials in 1 country	No
TAK-919 (Moderna formulation)	Takeda	RNA	Approved in 1 country	2 trials in 1 country	No
AWcorna	Walvax	RNA	Approved in 1 country	6 trials in 1 country	No
Covaxin	Bharat Biotech	Inactivated Virus	Approved in 14 countries	16 trials in 2 countries	Yes
KoviVac	Chumakov Center	Inactivated Virus	Approved in 3 countries	3 trials in 1 country (No trials for Phase 3)	No
Turkovac	Health Institutes of Turkey	Inactivated Virus	Approved in 1 country	8 trials in 1 country	No
FAKHRAVAC (MIVAC)	Organization of Defensive Innovation and Research	Inactivated Virus	Approved in 1 country	3 trials in 1 country	No
QazVac	Research Institute for Biological Safety Problems (RIBSP)	Inactivated Virus	Approved in 2 countries	3 trials in 1 country	No
KCONVAC	Shenzhen Kangtai Biological Products Co	Inactivated Virus	Approved in 2 countries	7 trials in 1 country	No
COVIran Barekat	Shifa Pharmed Industrial Co	Inactivated Virus	Approved in 1 country	6 trials in 1 country	No
Covilo	Sinopharm (Beijing)	Inactivated Virus	Approved in 93 countries	39 trials in 18 countries	Yes
Inactivated (Vero Cells)	Sinopharm (Wuhan)	Inactivated Virus	Approved in 2 countries	9 trials in 7 countries	No
CoronaVac	Sinovac	Inactivated Virus	Approved in 56 countries	42 trials in 10 countries	Yes
VLA2001	Valneva	Inactivated Virus	Approved in 33 countries	9 trials in 4 countries	No
iNCOVACC	Bharat Biotech	Non-Replicating Viral Vector	Approved in 1 country	4 trials in 1 country	No
Convidecia	CanSino	Non-Replicating Viral Vector	Approved in 10 countries	14 trials in 6 countries	Yes
Convidecia Air	CanSino	Non-Replicating Viral Vector	Approved in 2 countries	5 trials in 4 countries	No
Gam-COVID-Vac	Gamaleya	Non-Replicating Viral Vector	Approved in 1 country	2 trials in 1 country (No trials for Phase 3)	No
Sputnik Light	Gamaleya	Non-Replicating Viral Vector	Approved in 26 countries	7 trials in 3 countries	No
Sputnik V	Gamaleya	Non-Replicating Viral Vector	Approved in 74 countries	25 trials in 8 countries	No
Jcovden	Janssen (Johnson & Johnson)	Non-Replicating Viral Vector	Approved in 113 countries	26 trials in 25 countries	Yes
Vaxzevria	Oxford/AstraZeneca	Non-Replicating Viral Vector	Approved in 149 countries	73 trials in 34 countries	Yes
Covishield (Oxford/AstraZeneca formulation)	Serum Institute of India	Non-Replicating Viral Vector	Approved in 49 countries	6 trials in 1 country	Yes
Covifenz	Medicago	Virus-like Particles (VLP)	Approved in 1 country	6 trials in 6 countries	No
ZyCoV-D	Zydus Cadila	DNA	Approved in 1 country	6 trials in 1 country	No

Figure 1. Potential factors influencing the efficacy of the COVID-19 vaccine.

Table 2. Summarizes of the ongoing clinical trials testing the interaction between gut microbiota and COVID-19 vaccines.

Study title	Study type	Locations	Status	Study details	Results	Reference
Evaluation of the effect of Loigolactobacillus coryniformis K8 CECT 5711 consumption in health care workers exposed to COVID-19	Interventional study	Spain	Completed	The study population consisted of health care workers exposed to COVID-19 who were aged 18 years or older and had no history of COVID-19 infection or vaccination. The control group received a placebo capsule identical in appearance and taste to the intervention capsule for 12 weeks.	The probiotic L. coryniformis K8 CECT 5711 helps HCWs maintain their immune protection from the COVID-19 vaccine for longer.	^Citation36
Effect and Tolerability of a Nutritional Supplement Based on a Synergistic Combination of beta-Glucans and Selenium- and Zinc-Enriched Saccharomyces cerevisiae (ABB C1((R))) in Volunteers Receiving the Influenza or the COVID-19 Vaccine: A Randomized, Double-Blind, Placebo-Controlled Study	Interventional study	Spain	Completed	The study population consisted of healthy volunteers aged 18 to 65 years who received either the influenza vaccine (Chiromas®) or the COVID-19 vaccine (Comirnaty®). The control group received a placebo supplement identical in appearance and taste to the intervention supplement for the same duration as the intervention group.	The probiotic-based nutritional supplement ABB C1® could improve the efficiency of both the influenza and COVID-19 vaccines. This effect might relate with the modulation of gut microbiota dysbiosis by ABB C1®.	^Citation38
Association between Recent Usage of Antibiotics and Immunogenicity within Six Months after COVID-19 Vaccination	Interventional study	China	Completed	The study population consisted of 316 healthy volunteers aged 18 to 65 years who received the BNT162b2 vaccine against COVID-19. The control group consisted of 287 volunteers who had not used any antibiotics within six months before the first dose of the vaccine.	Recent antibiotic use may be associated with a lower seroconversion rate at day 21 (but not day 56 or 180) among BNT162b2 recipients.	^Citation39
Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin – study protocol for a pilot, multicentre, randomized, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients	Interventional study	Australia	Uncompleted	The study population consists of kidney transplant recipients who have received two doses of COVID-19 vaccine but have not developed protective immunity, defined as a neutralizing antibody titer of less than 30%. The control group receives a daily dose of maltodextrin (20 g) as a placebo for the same duration as the intervention group.	Not available	^Citation31
The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients	Observational study	United Kingdom	Completed	The study population consists of patients with inflammatory bowel disease (IBD) who are treated with infliximab and have received two doses of COVID-19 vaccine (either ChAdOx1 nCoV-19 or BNT162b2). The control group consists of patients who have a serological response below the geometric mean of the wider CLARITY-IBD cohort, defined as a neutralizing antibody titer of less than 30%.	there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response.	^Citation32
Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events.	Observational study	China	Completed	The study population consists of adults who have received either the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty) against SARS-CoV-2. The control group consists of patients who have a gut microbiota composition that is associated with poorer immune response and more adverse events to COVID-19 vaccination.	specific gut microbiota markers are associated with improved immune response and reduced adverse events following COVID-19 vaccines, suggesting that microbiota-targeted interventions may complement the effectiveness of COVID-19 vaccines.	^Citation42
Characterization of the Intestinal Microbiome in Healthy Adults over Sars-Cov-2 Vaccination	Observational study	Singapore	Completed	The study population consists of healthy adults who have received two doses of inactivated SARS-CoV-2 vaccine (BBIBP-CorV). The control group consists of patients who have a gut microbiota and metabolome profile that is associated with poorer serological response to COVID-19 vaccination.	The BBIBP-CorV vaccine could modulate the gut microbial composition and functions, which may help to protect against COVID-19.	^Citation30
The gut-microbiota-brain axis in a Spanish population in the aftermath of the COVID-19 pandemic: microbiota composition linked to anxiety, trauma, and depression profiles.	Observational study	Spain	Completed	The study population consists of adults from Spain who have experienced symptoms of anxiety, depression, or PTSD in the aftermath of the COVID-19 pandemic and/or previous traumatic events. The control group consists of patients who have a gut microbiota composition that is associated with higher levels of anxiety, depression, or PTSD symptoms.	gut microbes might affect anxiety, depression, and PTSD symptoms and COVID-19 vaccination might improve mental health by modulating gut microbial makeup.	^Citation43
Correlation of gut microbiota and metabolic functions with the antibody response to the BBIBP-CorV vaccine	Observational study	China	Completed	The study population consists of adults who have received two doses of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV; Sinopharm). The control group consists of patients who have a low antibody response to the BBIBP-CorV vaccine, defined as a neutralizing antibody titer of less than 30%.	gut microbes and their activities are linked to the BBIBP-CorV vaccine response, giving us clues for how to modulate gut microbes to improve the efficiency of current COVID-19 vaccines.	^Citation44
Dynamic changes in host immune system and gut microbiota are associated with the production of SARS-CoV-2 antibodies	Observational study	China	Completed	The study population consists of healthy adults who have received two doses of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV; Sinopharm). The control group consists of patients who do not have dynamic changes in their host immune system and gut microbiota that are associated with the production of SARS-CoV-2 antibodies.	gut microbiota and body features affect antibody production the most. This means that gut microbiota is important for making SARS-CoV-2 antibodies in young healthy people.	^Citation7
Gut Microbiota Profile and Its Impact on Immunity Status in COVID-19 Vaccinated Cohorts	Observational study	China	uncompleted	The study population consists of adults who have received either the mRNA vaccine (BNT162b2; Pfizer-BioNTech) or the adenovirus vector vaccine (ChAdOx1 nCoV-19; Oxford-AstraZeneca) against COVID-19.	Not available	ClinicalTrials.gov Identifier:NCT04980560
Modulation of Gut Microbiota to Enhance Health and Immunity	Interventional study	China	uncompleted	The study population consists of healthy adults who have no history of chronic diseases or gastrointestinal disorders. The control group receives a placebo for 12 weeks, with no effect on the gut microbiota or the health and immunity of the host.	Not available	ClinicalTrials.gov Identifier: NCT04884776
Modification of the COVID-19 Vaccine Response by an Intervention on the Intestinal Flora	Interventional study	Canada	uncompleted	The study population consists of adults who have received two doses of the mRNA vaccine (BNT162b2; Pfizer-BioNTech) against COVID-19. The control group receives a placebo supplement containing maltodextrin for 12 weeks, with no effect on the intestinal flora or the immune response to COVID-19 vaccination.	Not available	ClinicalTrials.gov Identifier: NCT05195151

Figure 2. Innate lymphocytes recognize increased opportunistic gut pathogens and intensify gut pro-inflammatory responses.

Figure 3. Depleted commensal symbionts negatively regulate the recruitment of immune cells.

Figure 4. Pattern recognition receptors are essential for the development of the immune system due to their innate sensing of the microbiota.

Figure 5. Antigen-presenting cells can be reprogrammed by microbiota.

Figure 6. Microbiota-derived metabolites modulate immune responses.

Figure 7. Antigens encoded by microbiota that are capable of cross-reactivity.

Figure 8. Potential gut microbiota-targeted interventions to improve the efficacy of COVID-19 vaccines.

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