HIV Vaccine Trial Exploits a Dual and Central Role for Innate Immunity

Limited understanding of correlates of protection from HIV transmission hinders development of an efficacious vaccine. D. J. M. Lewis and colleagues (J. Virol. 88:11648–11657, 2014, doi:10.1128/JVI.01621-14) now report that vaginal immunization with an HIVgp140 vaccine linked to the 70-kDa heat shock protein downregulated the human immunodeficiency virus (HIV) coreceptor CCR5 (chemokine [C-C motif] receptor 5) and increased expression of the HIV resistance factor APOBEC3G (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G), in women. These effects correlated with HIV suppression ex vivo. Thus, vaccine-induced innate responses not only facilitate adaptive immunity–they may prove to be critical for preventing HIV transmission.     

Evaluation of a Liposome-Supplemented Intranasal Influenza Subunit Vaccine in a Murine Model System: Induction of Systemic and Local Mucosal Immunity

Abstract

This study reports on the mucosal immunoadjuvant activity of liposomes in an experimental influenza subunit vaccine administered intranasally (i.n.) to mice. Antibody responses induced by the i.n. liposomal vaccine were compared to those induced by an influenza infection or by subcutaneous (s.c.) injection of subunit antigen alone, the conventional route of human flu vaccination. Negatively charged liposomes, but not positively charged or zwitter-ionic liposomes, coadministered i.n. with influenza subunit antigen, significantly stimulated systemic IgG levels and local antibody responses in pulmonary secretions, relative to the responses upon i.n. administration of subunit antigen alone. I.n. immunization with liposome-supplemented subunit antigen as well as s.c. immunization with subunit antigen alone or infection induced high levels of IgG antibodies in serum and pulmonary secretions, with a preferential induction of IgGl upon immunization and IgG2a upon infection. Both i.n. immunization with liposome-supplemented antigen and infection, but not s.c. immunization with subunit antigen alone, induced local secretion of S-IgA. At the same time, both IgA-and IgG-secreting cells appeared in (he lungs and lung-associated lymph nodes, suggestive of local antibody production. In conclusion, the liposomal adjuvant system, combined with a mucosal administration protocol, provides a promising strategy for induction of both systemic and local antibody responses against influenza virus.     

Liposomes as a Mucosal Adjuvant System: An Intranasal Liposomal Influenza Subunit Vaccine and the Role of IgA in Nasal Anti-Influenza Immunity

Abstract

Liposomes exhibit potent immunoadjuvant activity in a variety of experimental vaccine formulations. We have investigated the mucosal adjuvant activity of liposomes in an influenza subunit vaccine. Mice were immunized intranasally (I.N.) with the major surface antigen of influenza virus, hemagglutinin (HA), mixed with negatively charged liposomes. Inclusion of the liposomes in the vaccine resulted in a marked stimulation of the serum IgG response against the antigen. In addition, the liposomal preparation, but not the antigen alone, induced a significant secretory IgA (s-IgA) response, not only in the lungs and nasal cavity, but also at the mucosa of the urogenital tract. The adjuvant activity of the liposomes appeared to be independent of a physical association of the antigen with the liposomes: Stimulation of antibody responses was observed even when liposomes and antigen were administered separately in time. Serum IgG and local s-IgA responses to I.N. immunization with the liposomal vaccine were comparable to the corresponding responses induced by an influenza infection. Mice immunized with the liposomal vaccine or mice recovered from an influenza infection were completely protected from (re)infection. Protection from nasal infection was abrogated by treatment of the mice with an anti-IgA antiserum, while anti-IgG had no effect, indicating that s-IgA plays an essential role in nasal anti-influenza immunity.     

Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000–13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change—containing variation acquired from archaic hominins or adaptive variants in specific populations—improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.     

Pandemic Influenza H1N1 2009, Innate Immunity,and the Impact of Immunosenescence on Influenza Vaccine

Seasonal and pandemic strains of influenza have widespread implications for the global economy and global health. This has been highlighted recently as the epidemiologic characteristics for hospitalization and mortality for pandemic influenza H1N1 2009 are now emerging. While treatment with neuraminidase inhibitors are effective for seasonal and pandemic influenza, prevention of morbidity and mortality through effective vaccines requires a rigorous process of research and development. Vulnerable populations such as older adults (i.e., > age 65 years) suffer the greatest impact from seasonal influenza yet do not have a consistent seroprotective response to seasonal influenza vaccines due to a combination of factors. This short narrative review will highlight the emerging epidemiologic characteristics of pandemic H1N1 2009 and focus on immunosenescence, innate immune system responses to influenza virus infection and vaccination, and influenza vaccine responsiveness as it relates to seasonal and H1N1 pandemic influenza vaccines.     

Pseudotyped Influenza A Virus as a Vaccine for the Induction of Heterotypic Immunity

There is a need for vaccines that can protect broadly across all influenza A strains. We have produced a pseudotyped influenza virus based on suppression of the A/PR/8/34 hemagglutinin signal sequence (S-FLU) that can infect cells and express the viral core proteins and neuraminidase but cannot replicate. We show that when given by inhalation to mice, S-FLU is nonpathogenic but generates a vigorous T cell response in the lung associated with markedly reduced viral titers and weight loss after challenge with H1 and H3 influenza viruses. These properties of S-FLU suggest that it may have potential as a broadly protective A virus vaccine, particularly in the setting of a threatened pandemic before matched subunit vaccines become available.     

Characterization of a Surface Glycoprotein from Echinococcus multilocularis and Its Mucosal Vaccine Potential in Dogs

Alveolar echinococcosis is a refractory disease caused by the metacestode stage of Echinococcus multilocularis. The life cycle of this parasite is maintained primarily between foxes and many species of rodents; thus, dogs are thought to be a minor definitive host except in some endemic areas. However, dogs are highly susceptible to E. multilocularis infection. Because of the close contact between dogs and humans, infection of dogs with this parasite can be an important risk to human health. Therefore, new measures and tools to control and prevent parasite transmission required. Using 2-dimensional electrophoresis followed by western blot (2D-WB) analysis, a large glycoprotein component of protoscoleces was identified based on reactivity to intestinal IgA in dogs experimentally infected with E. multilocularis. This component, designated SRf1, was purified by gel filtration using a Superose 6 column. Glycosylation analysis and immunostaining revealed that SRf1 could be distinguished from Em2, a major mucin-type antigen of E. multilocularis. Dogs (n = 6) were immunized intranasally with 500 µg of SRf1 with cholera toxin subunit B by using a spray syringe, and a booster was given orally using an enteric capsule containing 15 mg of the same antigen. As a result, dogs immunized with this antigen showed an 87.6% reduction in worm numbers compared to control dogs (n = 5) who received only PBS administration. A weak serum antibody response was observed in SRf1-immunized dogs, but there was no correlation between antibody response and worm number. We demonstrated for the first time that mucosal immunization using SRf1, a glycoprotein component newly isolated from E. multilocularis protoscoleces, induced a protection response to E. multilocularis infection in dogs. Thus, our data indicated that mucosal immunization using surface antigens will be an important tool to facilitate the development of practical vaccines for definitive hosts.     

Effects of Psychological Stress on Innate Immunity and Metabolism in Humans: A Systematic Analysis

Stress is perhaps easiest to conceptualize as a process which allows an organism to accommodate for the demands of its environment such that it can adapt to the prevailing set of conditions. Psychological stress is an important component with the potential to affect physiology adversely as has become evident from various studies in the area. Although these studies have established numerous effects of psychological stress on physiology, a global strategy for the correlation of these effects has yet to begin. Our comparative and systematic analysis of the published literature has unraveled certain interesting molecular mechanisms as clues to account for some of the observed effects of psychological stress on human physiology. In this study, we attempt to understand initial phase of the physiological response to psychological stress by analyzing interactions between innate immunity and metabolism at systems level by analyzing the data available in the literature. In light of our gene association-networks and enrichment analysis we have identified candidate genes and molecular systems which might have some associative role in affecting psychological stress response system or even producing some of the observed terminal effects (such as the associated physiological disorders). In addition to the already accepted role of psychological stress as a perturbation that can disrupt physiological homeostasis, we speculate that it is potentially capable of causing deviation of certain biological processes from their basal level activity after which they can return back to their basal tones once the effects of stress diminish. Based on the derived inferences of our comparative analysis, we have proposed a probabilistic mechanism for how psychological stress could affect physiology such that these adaptive deviations are sometimes not able to bounce back to their original basal tones, and thus increase physiological susceptibility to metabolic and immune imbalance.     

Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

Background

Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.

Methods

Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.

Results

Vacc-4x proliferative T cell responses increased only among the vaccinated (p≤0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = −0.82, p<0.001) and high regulation (r = 0.61, p = 0.010) at baseline.

Conclusion

Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01473810","term_id":"NCT01473810"}}NCT01473810     

Asynchrony between Host Plant and Insects-Defoliator within a Tritrophic System: The Role of Herbivore Innate Immunity

The effects of asynchrony in the phenology of spring-feeding insect-defoliators and their host plants on insects’ fitness, as well as the importance of this effect for the population dynamics of outbreaking species of insects, is a widespread and well-documented phenomenon. However, the spreading of this phenomenon through the food chain, and especially those mechanisms operating this spreading, are still unclear. In this paper, we study the effect of seasonally declined leafquality (estimated in terms of phenolics and nitrogen content) on herbivore fitness, immune parameters and resistance against pathogen by using the silver birch Betula pendula—gypsy moth Lymantria dispar—nucleopolyhedrovirus as the tritrophic system. We show that a phenological mismatch induced by the delay in the emergence of gypsy moth larvae and following feeding on mature leaves has negative effects on the female pupal weight, on the rate of larval development and on the activity of phenoloxidase in the plasma of haemolymph. In addition, the larval susceptibility to exogenous nucleopolyhydrovirus infection as well as covert virus activation were both enhanced due to the phenological mismatch. The observed effects of phenological mismatch on insect-baculovirus interaction may partially explain the strong and fast fluctuations in the population dynamics of the gypsy moth that is often observed in the studied part of the defoliator area. This study also reveals some indirect mechanisms of effect related to host plant quality, which operate through the insect innate immune status and affect resistance to both exogenous and endogenous virus.