AIDS Vaccine Design Immunogenicity Efficacy
Tan, H. X., A. K. Wheatley, R. Esterbauer, S. Jegaskanda, J. J. Glass, D. Masopust, R. De Rose and S. J. Kent (2017). “Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime-boost immunization.” Mucosal Immunol.
Tissue-resident memory (TRM) CD8 T cells survey a range of non-lymphoid mucosal tissues where they rapidly mediate clearance of viral infections at the entry portals. Vaccines that establish CD8 TRM cells in the cervicovaginal mucosa hold promise for effective immunity against sexually transmitted HIV. We demonstrate that HIV-specific CD8 TRM cells can be established in the murine vaginal mucosa using a combined intranasal and intravaginal mucosal immunization with recombinant influenza-HIV vectors. Using in situ tetramer immunofluorescence microscopy, we found that this mucosally administered prime-boost immunization also resulted in the durable seeding of CD8 T cells in the frontline vaginal epithelial compartment as opposed to the vaginal submucosa. Upon cognate antigen recognition within the vaginal mucosa, these HIV-specific CD8 TRM cells rapidly initiated a tissue-wide state of immunity. The activation of HIV-specific CD8 TRM cells resulted in the upregulation of endothelial vessel addressin expression and substantial recruitment of both adaptive and innate immune cells in the vaginal mucosa. These findings suggest that the epithelial localization of HIV-specific CD8 TRM cell populations and their capacity to rapidly activate both arms of the immune system could significantly augment frontline defenses against vaginal HIV infection. Mucosal Immunology advance online publication 25 October 2017; doi:10.1038/mi.2017.89.
Emerging Infectious Diseases
Roberts, L. (2017). “Echoes of Ebola as plague hits Madagascar.” Science 358(6362): 430-431.
Allen, T., K. A. Murray, C. Zambrana-Torrelio, S. S. Morse, C. Rondinini, M. Di Marco, N. Breit, K. J. Olival and P. Daszak (2017). “Global hotspots and correlates of emerging zoonotic diseases.” Nat Commun 8(1): 1124.
Zoonoses originating from wildlife represent a significant threat to global health, security and economic growth, and combatting their emergence is a public health priority. However, our understanding of the mechanisms underlying their emergence remains rudimentary. Here we update a global database of emerging infectious disease (EID) events, create a novel measure of reporting effort, and fit boosted regression tree models to analyze the demographic, environmental and biological correlates of their occurrence. After accounting for reporting effort, we show that zoonotic EID risk is elevated in forested tropical regions experiencing land-use changes and where wildlife biodiversity (mammal species richness) is high. We present a new global hotspot map of spatial variation in our zoonotic EID risk index, and partial dependence plots illustrating relationships between events and predictors. Our results may help to improve surveillance and long-term EID monitoring programs, and design field experiments to test underlying mechanisms of zoonotic disease emergence.
Romero-Alvarez, D., J. Reyes, V. Quezada, C. Satan, N. Cevallos, S. Barrera, G. Trueba, L. E. Escobar and J. E. Villacis (2017). “First case of New Delhi metallo-beta-lactamase in Klebsiella pneumoniae from Ecuador: an update for South America.” Int J Infect Dis.
OBJECTIVES: To describe a clinical case of Klebsiella pneumoniae harboring New Delhi metallo-beta-lactamase (NDM) plasmid in Ecuador and to present a map of reports of NDM isolates in South America. METHODS: We used the Modified Hodge Test, Carbapenem Inactivation Method, the synergy with imipenem-EDTA disk method, and Rapidec Carba NP for identification of antibiotic resistance mechanisms. The presence of resistant genes was explored with a conjugation assay, and molecular confirmation of NDM with PCR and DNA sequencing. Plasmid characterization was performed with PBRT. Literature review for reports in South America was performed in Google Scholar and PubMed. RESULTS: An HIV patient that has never traveled abroad developed a blood stream infection caused by K. pneumoniae ST147 harboring the NDM-1 resistant gene in a plasmid from the IncA/C group. Local circulation of NDM has also been described in other South American countries especially in Colombia and Brazil although we did not find scientific published records from other countries. CONCLUSIONS: We present the first evidence of autochthonous circulation of the NDM-1 resistant gene harbored by an IncA/C plasmid isolated from a K. pneumoniae ST147 in Ecuador. Efforts should be implemented to monitor and characterize the spatial and temporal distribution of NDM in Ecuador and other countries of South America.
Grifoni, A., M. A. Angelo, B. Lopez, P. H. O’Rourke, J. Sidney, C. Cerpas, A. Balmaseda, C. G. T. Silveira, A. Maestri, P. R. Costa, A. P. Durbin, S. A. Diehl, E. Phillips, S. Mallal, A. D. De Silva, G. Nchinda, C. Nkenfou, M. H. Collins, A. M. de Silva, M. Q. Lim, P. A. Macary, F. Tatullo, T. Solomon, V. Satchidanandam, A. Desai, V. Ravi, J. Coloma, L. Turtle, L. Rivino, E. G. Kallas, B. Peters, E. Harris, A. Sette and D. Weiskopf (2017). “Global Assessment of Dengue Virus-Specific CD4+ T Cell Responses in Dengue-Endemic Areas.” Front Immunol 8: 1309.
BACKGROUND: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+ T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua. METHODS: HLA class II epitopes in the population of Managua were identified by an in vitro IFNgamma ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a “megapool” (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by intracellular cytokine staining assays. RESULTS: We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naive subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency >/=5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles). CONCLUSION: The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.
HIV – Africa
Cabral, A., J. Baeten, K. Ngure, J. Velloza, J. Odoyo, J. Haberer, C. Celum, T. Muwonge, S. Asiimwe and R. Heffron (2017). “Intimate partner violence and self-reported pre-exposure prophylaxis (PrEP) interruptions among HIV-negative partners in HIV serodiscordant couples in Kenya and Uganda.” J Acquir Immune Defic Syndr.
BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is effective for HIV prevention and PrEP delivery studies are investigating ways to deliver PrEP with high adherence. However, in many settings with high HIV burden, intimate partner violence (IPV) is reported often and could be a barrier to effective PrEP use. We examined the association between IPV and interruptions in PrEP use. METHODS: We analyzed data from 1,013 serodiscordant heterosexual couples enrolled in a large PrEP demonstration project in Kenya and Uganda, the Partners Demonstration Project. At quarterly study visits, HIV-negative participants receiving PrEP were asked about interruptions in their PrEP use and experiences with IPV. The association between IPV and PrEP interruptions was analyzed using multivariable generalized estimating equations. RESULTS: At baseline and follow-up there were 53 visits with reports of abuse by 49 HIV-negative partners, including physical, economic, and verbal IPV. Interruptions in PrEP use were reported at 328 visits (7.1% of all visits) by 249 people. The median length of PrEP interruption was 28 days (interquartile range [IQR]: 7-45). The frequency of PrEP interruptions among those reporting IPV was 23.8% and those without IPV was 6.9%. PrEP interruption was significantly associated with IPV after adjustment for age and frequency of sexual intercourse (adjusted OR=2.6, 95% CI 1.2-6.0). CONCLUSION: IPV was more likely to be reported at visits when PrEP interruptions were also reported, which may have implications for sustained adherence to PrEP. Within PrEP delivery programs, there may be opportunities to assess individual safety and well-being in order to bolster adherence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
HIV – Cures & Treatments
Hsu, D. C. and J. Ananworanich (2017). “Immune Interventions to Eliminate the HIV Reservoir.” Curr Top Microbiol Immunol.
Inducing HIV remission is a monumental challenge. A potential strategy is the “kick and kill” approach where latently infected cells are first activated to express viral proteins and then eliminated through cytopathic effects of HIV or immune-mediated killing. However, pre-existing immune responses to HIV cannot eradicate HIV infection due to the presence of escape variants, inadequate magnitude, and breadth of responses as well as immune exhaustion. The two major approaches to boost immune-mediated elimination of infected cells include enhancing cytotoxic T lymphocyte mediated killing and harnessing antibodies to eliminate HIV. Specific strategies include increasing the magnitude and breadth of T cell responses through therapeutic vaccinations, reversing the effects of T cell exhaustion using immune checkpoint inhibition, employing bispecific T cell targeting immunomodulatory proteins or dual-affinity re-targeting molecules to direct cytotoxic T lymphocytes to virus-expressing cells and broadly neutralizing antibody infusions. Methods to steer immune responses to tissue sites where latently infected cells are located need to be further explored. Ultimately, strategies to induce HIV remission must be tolerable, safe, and scalable in order to make a global impact.
HIV – HLA
Parolini, F., P. Biswas, M. Serena, F. Sironi, V. Muraro, E. Guizzardi, L. Cazzoletti, M. T. Scupoli, D. Gibellini, E. Ugolotti, R. Biassoni, A. Beretta, M. Malnati, M. G. Romanelli and D. Zipeto (2017). “Stability and expression levels of HLA-C on the cell membrane modulate HIV-1 infectivity.” J Virol.
HLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to a better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes (CTLs), as well as the triggering of activating Killer Immunoglobulin like receptors (KIR) on NK-cells, whereas lower levels may provide a poor HIV-1 control and a rapid progression toward AIDS. We characterized the relative amount of HLA-C heterotrimers (heavy chain/beta2m/peptide) and HLA-C free heavy chains on PBMC from healthy blood donors harboring both alleles with stable or unstable binding to beta2m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMC with various allotypes. We observed significant differences in HLA-C heterotrimers stability and in expression levels. We found that R5 HIV-1 virions produced by PBMC harboring unstable HLA-C alleles were more infectious than those produced by PBMC carrying the stable variants. We propose that HIV-1 infectivity might depend both on the amounts of HLA-C molecules and on their stability as trimeric complex. According to this model, individuals with low expressed HLA-C alleles and unstable binding to beta2m/peptide might have a worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication. IMPORTANCE Following HIV-1 infection, some people advance rapidly toward AIDS while others have a slow disease progression. HLA-C, a molecule involved in immunity, is a key determinant of HIV-1 control. Here we reveal how HLA-C variants contribute to modulate viral infectivity. HLA-C is present on the cell surface in two different conformations: the immunologically active conformation is part of a complex that includes beta2-microglobulin/peptide; the other conformation is not bound to beta2-microglobulin/peptide and can associate with HIV-1, increasing its infectivity. Individuals with HLA-C variants with a predominance of immunologically active conformations would display a stronger immunity against HIV-1, a reduced viral infectivity and an effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from beta2-microglobulin/peptide would have a reduced immunological response to HIV-1 and produce more infectious virions. This study provides new information that could be useful to design novel vaccine strategies and therapeutic approaches against HIV-1.
HIV – IMMUNE ACTIVATION
Veenhuis, R. T., Z. T. Freeman, J. Korleski, L. K. Cohen, G. Massaccesi, A. Tomasi, A. W. Boesch, M. E. Ackerman, J. B. Margolick, J. N. Blankson, M. A. Chattergoon and A. L. Cox (2017). “HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells.” J Clin Invest.
Type I IFN production is essential for innate control of acute viral infection; however, prolonged high-level IFN production is associated with chronic immune activation in HIV-infected individuals. Although plasmacytoid DCs (pDCs) are a primary source of IFN, the mechanisms that regulate IFN levels following the acute phase are unknown. We hypothesized that HIV-specific Ab responses regulate late IFN production. We evaluated the mechanism through which HIV-activated pDCs produce IFN as well as how both monoclonal HIV-specific Abs and Abs produced in natural HIV infection modulated normal pDC sensing of HIV. We found that HIV-induced IFN production required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or HIV life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding markedly enhanced the IFN response, irrespective of their ability to neutralize CD4+ T cell infection. Ab-mediated enhancement of IFN production required Fc gamma receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized in the absence of Ab. Polyclonal Abs isolated from HIV-infected subjects also enhanced pDC production of IFN in response to HIV. Our data provide an explanation for high levels of IFN production and immune activation in chronic HIV infection.
Saha, J. M., H. Liu, P. W. Hu, B. C. Nikolai, H. Wu, H. Miao and A. P. Rice (2017). “Proteomic profiling of a primary CD4+ T cell model of HIV-1 latency identifies proteins whose differential expression correlates with reactivation of latent HIV-1.” AIDS Res Hum Retroviruses.
The latent HIV-1 reservoir of memory CD4+ T cells that persists during combination antiviral therapy prevents a cure of infection. Insight into mechanisms of latency and viral reactivation are essential for the rationale design of strategies to reduce the latent reservoir. In this study, we quantified the levels of over 2,600 proteins in the CCL19 primary CD4+ T cell model of HIV-1 latency. We profiled proteins under conditions that promote latent infection and after cells were treated with PMA + ionomycin which is known to efficiently induce reactivation of latent HIV-1. In an analysis of cells from two healthy blood donors, we identified 61 proteins that were up-regulated >2-fold, and 36 proteins that were down-regulated >2-fold under conditions in which latent viruses were reactivated. These differentially expressed proteins are therefore candidates for cellular factors that regulate latency or viral reactivation. Two unexpected findings were obtained from the proteomic data: 1) the interactions among the majority of up-regulated proteins are largely undetermined in published protein-protein interaction (PPI) networks; 2) down-regulated proteins are strongly associated with Gene Ontology (GO) terms related to mitochondrial protein synthesis. This proteomic dataset provides a useful resource for future mechanistic studies of HIV-1 latency.
Peppa, D. (2017). “Natural Killer Cells in Human Immunodeficiency Virus-1 Infection: Spotlight on the Impact of Human Cytomegalovirus.” Front Immunol 8: 1322.
Human cytomegalovirus (HCMV) has been closely associated with the human race across evolutionary time. HCMV co-infection is nearly universal in human immunodeficiency virus-1 (HIV-1)-infected individuals and remains an important cofactor in HIV-1 disease progression even in the era of effective antiretroviral treatment. HCMV infection has been shown to have a broad and potent influence on the human immune system and has been linked with the discovery and characterization of adaptive natural killer (NK) cells. Distinct NK-cell subsets, predominately expressing the activating receptor NKG2C and the marker of terminal differentiation CD57, expand in response to HCMV. These NK-cell populations engaged in the long-lasting interaction with HCMV, in addition to characteristic but variable expression of surface receptors, exhibit reduced expression of signaling proteins and transcription factors expressed by canonical NK cells. Broad epigenetic modifications drive the emergence and persistence of HCMV-adapted NK cells that have distinct functional characteristics. NKG2C+ NK-cell expansions have been observed in HIV-1 infected patients and other acute and chronic viral infections being systematically associated with HCMV seropositivity. The latter is potentially an important confounding variable in studies focused on the cellular NK-cell receptor repertoire and functional capacity. Here, focusing on HIV-1 infection we review the evidence in favor of “adaptive” changes likely induced by HCMV co-infection in NK-cell subsets. We highlight a number of key questions and how insights into the adaptive behavior of NK cells will inform new strategies exploiting their unique properties in the fight against HIV-1.
Darcis, G., B. Van Driessche, S. Bouchat, F. Kirchhoff and C. Van Lint (2017). “Molecular Control of HIV and SIV Latency.” Curr Top Microbiol Immunol.
The HIV latent reservoirs are considered as the main hurdle to viral eradication. Numerous mechanisms lead to the establishment of HIV latency and act at the transcriptional and post-transcriptional levels. A better understanding of latency is needed in order to ultimately achieve a cure for HIV. The mechanisms underlying latency vary between patients, tissues, anatomical compartments, and cell types. From this point of view, simian immunodeficiency virus (SIV) infection and the use of nonhuman primate (NHP) models that recapitulate many aspects of HIV-associated latency establishment and disease progression are essential tools since they allow extensive tissue sampling as well as a control of infection parameters (virus type, dose, route, and time).
HIV – Neutralizing Antibodies
Cohen, M. S. and L. Corey (2017). “Broadly neutralizing antibodies to prevent HIV-1.” Science 358(6359): 46-47.
Crunkhorn, S. (2017). “HIV: Trispecific antibodies block infection.” Nat Rev Drug Discov 16(11): 754.
HIV – PrEP
Markowitz, M., H. Grossman, P. L. Anderson, R. Grant, M. Gandhi, H. Horng and H. Mohri (2017). “Newly Acquired Infection With Multidrug-Resistant HIV-1 in a Patient Adherent to Preexposure Prophylaxis.” J Acquir Immune Defic Syndr 76(4): e104-e106.
Abaasa, A., C. Hendrix, M. Gandhi, P. Anderson, A. Kamali, F. Kibengo, E. J. Sanders, G. Mutua, N. N. Bumpus, F. Priddy and J. E. Haberer (2017). “Utility of Different Adherence Measures for PrEP: Patterns and Incremental Value.” AIDS Behav.
Measuring PrEP adherence remains challenging. In 2009-2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP.
Viciana, P. (2017). “Rilpivirine: The Key for Long-term Success.” AIDS Rev 19(3): 156-166.
During the past 30 years of antiretroviral therapy, continuous improvements in drug discovery have provided increasingly potent and safer antivirals that have transformed HIV infection in a chronic illness, rarely fatal. Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are frequently used as part of any antiretroviral combination therapy. Side effects and low resistance barrier of fi rst-generation NNRTIs (e.g., nevirapine and efavirenz) have been overcome with rilpivirine (RPV), and the last NNRTI approved for the treatment of HIV infection. The good efficacy, safety profi le, and convenient dosing of RPV account for the unique durability of RPV-based regimens. The advent of new oral fi xed-dose coformulations of RPV (e.g., along with dolutegravir or with tenofovir alafenamide [TAF]/emtricitabine [FTC]) as well as the development of long-acting injectable RPV nanoformulations will further expand its therapeutic landscape, including RPV use in dual maintenance therapy in HIV-infected patients or as pre-exposure prophylaxis in high-risk uninfected individuals.
Markowitz, M., H. Grossman, P. L. Anderson, R. Grant, M. Gandhi, H. Horng and H. Mohri (2017). “Newly Acquired Infection With Multidrug-Resistant HIV-1 in a Patient Adherent to Preexposure Prophylaxis.” J Acquir Immune Defic Syndr 76(4): e104-e106.
Ghulam-Smith, M., A. Olson, L. F. White, C. S. Chasela, S. R. Ellington, A. P. Kourtis, D. J. Jamieson, G. Tegha, C. M. van der Horst and M. Sagar (2017). “Maternal but Not Infant Anti-HIV-1 Neutralizing Antibody Response Associates with Enhanced Transmission and Infant Morbidity.” MBio 8(5).
A significant number of infants acquire HIV-1 through their infected mother’s breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) (n = 42), compared to those that eventually acquired infection (n = 21), did not possess higher nAb responses against heterologous envelopes (P = 0.46) or their mothers’ variants (P = 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (P = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (P = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (P = 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity. IMPORTANCE Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby.
Vaccine Design Adjuvants
Bolhassani, A., S. Talebi and A. Anvar (2017). “Endogenous and Exogenous Natural Adjuvants for Vaccine Development.” Mini Rev Med Chem 17(15): 1442-1456.
Objective & Background: Various adjuvants are usually co-injected with an antigen for stimulation of effective immune responses. Adjuvants are able to elicit innate immune responses at the injection site. Depending on the activated type of innate responses, adjuvants can modify the quality and quantity of adaptive immune responses. Their mechanisms of action in vaccine development include: a) enhancement of the total antibody titers; b) reduction of the antigen dose; c) induction of potent cell-mediated immunity; d) increase in the speed and duration of the protective response; e) stimulation of mucosal immunity; and f) cross-protection. Up to now, different exogenous adjuvants have been identified to boost immune responses including inorganic compounds, mineral oil, bacterial products, non-bacterial organics, detergents or Quil A, plant saponins, Freund’s complete or incomplete adjuvants, and delivery systems. However, some immune responses can be generated in the absence of the exogenous adjuvants. Indeed, endogenous adjuvants released from the cells were known as the danger signals and immunogenic compounds. Several main endogenous adjuvants contain cytokines, chemokines, alarmins, dendritic cells (DCs), toll like receptor (TLR) ligands or agonists, and antibodies. RESULTS & CONCLUSION: In this review, the immune activities of the natural adjuvants especially endogenous adjuvants and their mechanisms of action are discussed.
VACCINE DESIGN IMMUNOGENICITY EFFICACY
Bogdanoff, W. A., E. I. Perez, T. Lopez, C. F. Arias and R. M. DuBois (2017). “Structural basis for the escape of human astrovirus from antibody neutralization: broad implications for rational vaccine design.” J Virol.
Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection, however antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (mAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid’s spike domain. To understand the molecular basis for resistance from mAb PL-2 neutralization, we determined the 1.35 A-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by mAb PL-2. We show that mutation to serine permits loop flexibility and recovers mAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our results have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations. IMPORTANCE Human astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.
Platteel, A. C. M., S. Henri, D. M. Zaiss and A. Sijts (2017). “Dissecting antigen processing and presentation routes in dermal vaccination strategies.” Vaccine.
The skin is an attractive site for vaccination due to its accessibility and presence of immune cells surveilling this barrier. However, knowledge of antigen processing and presentation upon dermal vaccination is sparse. In this study we determined antigen processing routes that lead to CD8+ T cell activation following dermal DNA tattoo immunization, exploiting a model antigen that contains an immunoproteasome-dependent epitope. In agreement with earlier reports, we found that DNA tattoo immunization of wild type (WT) mice triggered vigorous responses to the immunoproteasome-dependent model epitope, whereas gene-deficient mice lacking the immunoproteasome subunits beta5i/LMP7 and beta2i/MECL1 failed to respond. Unexpectedly, dermal immunization both of irradiated bone marrow (BM) reconstituted mice in which the BM transplant was of WT origin, and of WT mice transplanted with immunoproteasome subunit-deficient BM induced a CD8+ T cell response to the immunoproteasome-dependent epitope, implying that both BM and host-derived cells contributed to processing of delivered model antigen. Depletion of radiation-resistant Langerhans cells (LC) from chimeric mice did not diminish tattoo-immunization induced CD8+ T cell responses in most mice, illustrating that LC were not responsible for antigen processing and CD8+ T cell priming in tattoo-immunized hosts. We conclude that both BM and non-BM-derived cells contribute to processing and cross-presentation of antigens delivered by dermal DNA tattoo immunization.
Nordstrom, T., M. Pandey, A. Calcutt, J. Powell, Z. N. Phillips, G. Yeung, A. K. Giddam, Y. Shi, T. Haselhorst, M. von Itzstein, M. R. Batzloff and M. F. Good (2017). “Enhancing Vaccine Efficacy by Engineering a Complex Synthetic Peptide To Become a Super Immunogen.” J Immunol 199(8): 2794-2802.
Peptides offer enormous promise as vaccines to prevent and protect against many infectious and noninfectious diseases. However, to date, limited vaccine efficacy has been reported and none have been licensed for human use. Innovative ways to enhance their immunogenicity are being tested, but rational sequence modification as a means to improve immune responsiveness has been neglected. Our objective was to establish a two-step generic protocol to modify defined amino acids of a helical peptide epitope to create a superior immunogen. Peptide variants of p145, a conserved helical peptide epitope from the M protein of Streptococcus pyogenes, were designed by exchanging one amino acid at a time, without altering their alpha-helical structure, which is required for correct antigenicity. The immunogenicities of new peptides were assessed in outbred mice. Vaccine efficacy was assessed in a skin challenge and invasive disease model. Out of 86 variants of p145, seven amino acid substitutions were selected and made the basis of the design for 18 new peptides. Of these, 13 were more immunogenic than p145; 7 induced Abs with significantly higher affinity for p145 than Abs induced by p145 itself; and 1 peptide induced more than 10,000-fold greater protection following challenge than the parent peptide. This peptide also only required a single immunization (compared with three immunizations with the parent peptide) to induce complete protection against invasive streptococcal disease. This study defines a strategy to rationally improve the immunogenicity of peptides and will have broad applicability to the development of vaccines for infectious and noninfectious diseases.
Vaccine Design – Vectors
Ewer, K., S. Sebastian, A. J. Spencer, S. Gilbert, A. V. S. Hill and T. Lambe (2017). “Chimpanzee Adenoviral Vectors as Vaccines for Outbreak Pathogens.” Hum Vaccin Immunother: 0.
The 2014-15 Ebola outbreak in West Africa highlighted the potential for large disease outbreaks caused by emerging pathogens and has generated considerable focus on preparedness for future epidemics. Here we discuss drivers, strategies and practical considerations for developing vaccines against outbreak pathogens. Chimpanzee adenoviral (ChAd) vectors have been developed as vaccine candidates for multiple infectious diseases and prostate cancer. ChAd vectors are safe and induce antigen-specific cellular and humoral immunity in all age groups, as well as circumventing the problem of pre-existing immunity encountered with human Ad vectors. For these reasons, such viral vectors provide an attractive platform for stockpiling vaccines for emergency deployment in response to a threatened outbreak of an emerging pathogen. Work is already underway to develop vaccines against a number of other outbreak pathogens and we will also review progress on these approaches here, particularly for Lassa fever, Nipah and MERS.