Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques.

The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7 + effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity.IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses

Impact of Th1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques.

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses.IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine

A pandemic recap : lessons we have learned

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.Non peer reviewe

Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques.

The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7+ effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity.IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses

HIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge

The oral mucosa is an attractive site for mucosal vaccination, however the thick squamous epithelium limits antigen uptake. Here we utilize a modified needle-free injector to deliver immunizations to the sublingual and buccal (SL/B) tissue of rhesus macaques. Needle-free SL/B vaccination with modified vaccinia Ankara (MVA) and a recombinant trimeric gp120 protein generates strong vaccine-specific IgG responses in serum as well as vaginal, rectal and salivary secretions. Vaccine-induced IgG responses show a remarkable breadth against gp70-V1V2 sequences from multiple clades of HIV-1. In contrast, topical SL/B immunizations generates minimal IgG responses. Following six intrarectal pathogenic SHIV-SF162P3 challenges, needle-free but not topical immunization results in a significant delay of acquisition of infection. Delay of infection correlates with non-neutralizing antibody effector function, Env-specific CD4(+) T-cell responses, and gp120 V2 loop specific antibodies. These results demonstrate needle-free MVA/gp120 oral vaccination as a practical and effective route to induce protective immunity against HIV-1

Impact of Th1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques.

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses.IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine

A pandemic recap: lessons we have learned

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making