AIDS Vaccine Clinical Trials
McGuire, E. P., Y. Fong, C. Toote, C. K. Cunningham, E. J. McFarland, W. Borkowsky, S. Barnett, H. L. Itell, A. Kumar, G. Gray, M. J. McElrath, G. D. Tomaras, S. R. Permar and G. G. Fouda (2017). “HIV exposed infants vaccinated with a MF59/rgp120 vaccine have higher magnitude anti-V1V2 IgG responses than adults immunized with the same vaccine.” J Virol.
In the RV144 vaccine trial, IgG responses against the HIV envelope variable loops 1 and 2 (V1V2) were associated with decreased HIV acquisition risk. We previously reported that infants immunized with a MF59 adjuvanted rgp120 vaccine developed higher magnitude anti-V1V2 IgG responses than adult RV144 vaccinees. To determine if the robust antibody response in infants is due to differences in vaccine regimens or to inherent differences between the adult and infant immune systems, we compared Env-specific IgG responses in adults and infants immunized with the same MF59 and Alum adjuvanted HIV envelope vaccines. At peak immunogenicity, the magnitude of gp120 and V1V2-specific IgG responses was comparable between adults and infants immunized with the Alum/MNrg120 vaccine (gp120 median MFI infant: 7,118; adult: 11,510; p=0.070; V1V2 median MFI infant: 512; adult: 804;; p=0.50), whereas infants immunized with the MF59/SF-2 rgp120 vaccine had higher magnitude antibody levels than adults (gp120 median MFI infant: 15,509; adult: 2,290; p<0.001; V1V2 median MFI infant: 23,926; adult: 1538; p<0.001). Six months after peak immunogenicity, infants maintained higher levels Env-specific IgG than adults. Anti-V1V2 IgG3 antibodies that were associated with decreased HIV-1 risk in RV144 vaccinees were present in 43% of MF59/rgp120 vaccinated infants but only in 12% of the vaccinated adults (p=0.0018). Finally, in contrast to rare vaccine-elicited Env-specific IgA in infants, rg120 vaccination elicited Env-specific IgA were frequently detected in adults. Our results suggest that vaccine adjuvants differently modulate gp120-specific antibody responses in adults and infants, and that infants can robustly respond to HIV Env immunization. IMPORTANCE: More than 150,000 pediatric HIV infections continue to occur yearly, despite the availability of antiretroviral prophylaxis. A pediatric HIV vaccine could reduce the number of these ongoing infant infections, and also prime for long term immunity prior to sexual debut. We previously reported that immunization of infants with a MF59 adjuvanted recombinant gp120 vaccine induced higher magnitude potentially protective anti-V1V2 IgG responses than in adult vaccinees receiving the moderately effective RV144 vaccine. In the present study, we demonstrate that the robust response observed in infants is not due to differences in vaccine regimen or vaccine dose between adults and infants. Our results suggest that HIV vaccine adjuvants may differentially modulate immune responses in adults and infants, highlighting the need to conduct vaccine trials in pediatric populations.
Haidari, G., A. Cope, A. Miller, S. Venables, C. Yan, H. Ridgers, K. Reijonen, D. Hannaman, A. Spentzou, P. Hayes, G. Bouliotis, A. Vogt, S. Joseph, B. Combadiere, S. McCormack and R. J. Shattock (2017). “Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial.” Sci Rep 7(1): 13011.
Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-gamma responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers.
AIDS Vaccine Design Immunogenicity Efficacy
Cutrell, A., D. Donnell, D. T. Dunn, D. V. Glidden, A. Grobler, B. Hanscom, B. S. Stancil, R. D. Meyer, R. Wang and R. L. Cuffe (2017). “HIV prevention trial design in an era of effective pre-exposure prophylaxis.” HIV Clin Trials: 1-12.
Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.
Shen, X., R. Basu, S. Sawant, D. Beaumont, S. F. Kwa, C. LaBranche, K. E. Seaton, N. L. Yates, D. C. Montefiori, G. Ferrari, L. S. Wyatt, B. Moss, S. M. Alam, B. F. Haynes, G. D. Tomaras and H. L. Robinson (2017). “HIV-1 gp120 Protein and MVAgp140 Boost Immunogens Increase immunogenicity of a DNA/MVA HIV-1 Vaccine.” J Virol.
An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia Ankara (MVA) expressing HIV-1 Env on virus like particles. Here we evaluated whether the addition of a gp120 protein in alum or MVA expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime – MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26 and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low titer tier 1B and Tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses; whereas, the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4+ T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4+ T cell responses. IMPORTANCE: Prior immune correlates analyses in humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime – modified vaccinia Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime – MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4+ T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.
Yu, T., L. Wu and P. B. Gilbert (2017). “A joint model for mixed and truncated longitudinal data and survival data, with application to HIV vaccine studies. “Biostatistics.
In HIV vaccine studies, a major research objective is to identify immune response biomarkers measured longitudinally that may be associated with risk of HIV infection. This objective can be assessed via joint modeling of longitudinal and survival data. Joint models for HIV vaccine data are complicated by the following issues: (i) left truncations of some longitudinal data due to lower limits of quantification; (ii) mixed types of longitudinal variables; (iii) measurement errors and missing values in longitudinal measurements; (iv) computational challenges associated with likelihood inference. In this article, we propose a joint model of complex longitudinal and survival data and a computationally efficient method for approximate likelihood inference to address the foregoing issues simultaneously. In particular, our model does not make unverifiable distributional assumptions for truncated values, which is different from methods commonly used in the literature. The parameters are estimated based on the h-likelihood method, which is computationally efficient and offers approximate likelihood inference. Moreover, we propose a new approach to estimate the standard errors of the h-likelihood based parameter estimates by using an adaptive Gauss-Hermite method. Simulation studies show that our methods perform well and are computationally efficient. A comprehensive data analysis is also presented.
Williams, W. B., Q. Han and B. F. Haynes (2017). “Cross-reactivity of HIV vaccine responses and the microbiome.” Curr Opin HIV AIDS.
PURPOSE OF REVIEW: A successful HIV-type 1 (HIV-1) vaccine will require immunogens that induce protective immune responses. However, recent studies suggest that the response to HIV-1 and perhaps other viruses may be altered by immune system exposure to intestinal microbiota-antigens. This review will discuss select aspects of these studies. RECENT FINDINGS: Naive CD4 T and B cell repertoires can be imprinted by intestinal microbiota-antigens to respond to virus epitopes prior to virus infection. A multiclade envelope (Env) gp145 DNA prime, recombinant adenovirus type 5 boost vaccine tested in a HIV Vaccine Trials Network (HVTN) phase IIb human vaccine efficacy trial (HVTN 505) induced a dominant gp41-reactive antibody response that was non-neutralizing and cross-reactive with intestinal microbiota. This vaccine regimen also induced a dominant gp41-reactive, intestinal microbiota-cross-reactive gp41 antibody response in neonatal and adult Rhesus macaques. Studies of naive CD4 T cells have demonstrated cross-reactivity to both HIV-1 and influenza peptides. SUMMARY: HIV-1 Env vaccine-induced CD4 T and B cell responses can originate from a pool of intestinal microbiota-cross-reactive immune cells. Moreover, intestinal microbiota-cross-reactive HIV-1 Env antibodies are ineffective in protection against HIV-1 infection. Thus, intestinal microbiota-imprinting of the B cell repertoire may be one of several roadblocks to the induction of protective HIV-1 antibodies.
Emerging Infectious Diseases Vaccine Design
Cashman, K. A., E. R. Wilkinson, C. I. Shaia, P. R. Facemire, T. M. Bell, J. J. Bearss, J. D. Shamblin, S. E. Wollen, K. E. Broderick, N. Y. Sardesai and C. S. Schmaljohn (2017). “A DNA vaccine delivered by dermal electroporation fully protects cynomolgus macaques against Lassa fever.” Hum Vaccin Immunother: 0.
Lassa virus (LASV) is an ambisense RNA virus in the Arenaviridae family and is the etiological agent of Lassa fever, a severe hemorrhagic disease endemic to West and Central Africa 1,2 . There are no U.S. Food and Drug Administration (FDA)-licensed vaccines available to prevent Lassa fever 1,2 . in our previous studies, we developed a gene-optimized DNA vaccine that encodes the glycoprotein precursor gene of LASV (Josiah strain) and demonstrated that three vaccinations accompanied by dermal electroporation protected guinea pigs from LASV-associated illness and death. Here, we describe an initial efficacy experiment in cynomolgus macaque nonhuman primates (NHPs) in which we followed an identical 3-dose vaccine schedule that was successful in guinea pigs, and a follow-on experiment in which we employed an accelerated vaccination strategy consisting of two administrations, spaced four weeks apart. In both studies, all of the LASV DNA-vaccinated NHPs survived challenge and none of them had measureable, sustained viremia or displayed weight loss or other disease signs post-exposure. Three of 10 mock-vaccinates survived exposure to LASV, but all of them became acutely ill post-exposure and remained chronically ill to the study endpoint (45 days post-exposure). Two of the three survivors experienced sensorineural hearing loss (described elsewhere). These results clearly demonstrate that the LASV DNA vaccine combined with dermal electroporation is a highly effective candidate for eventual use in humans.
Yi, G., X. Xu, S. Abraham, S. Petersen, H. Guo, N. Ortega, P. Shankar and N. Manjunath (2017). “A DNA Vaccine Protects Human Immune Cells against Zika Virus Infection in Humanized Mice.” EBioMedicine.
A DNA vaccine encoding prM and E protein has been shown to induce protection against Zika virus (ZIKV) infection in mice and monkeys. However, its effectiveness in humans remains undefined. Moreover, identification of which immune cell types are specifically infected in humans is unclear. We show that human myeloid cells and B cells are primary targets of ZIKV in humanized mice. We also show that a DNA vaccine encoding full length prM and E protein protects humanized mice from ZIKV infection. Following administration of the DNA vaccine, humanized DRAG mice developed antibodies targeting ZIKV as measured by ELISA and neutralization assays. Moreover, following ZIKV challenge, vaccinated animals presented virtually no detectable virus in human cells and in serum, whereas unvaccinated animals displayed robust infection, as measured by qRT-PCR. Our results utilizing humanized mice show potential efficacy for a targeted DNA vaccine against ZIKV in humans.
Gsell, P. S., A. Camacho, A. J. Kucharski, C. H. Watson, A. Bagayoko, S. Danmadji, N. E. Dean, A. Diallo, A. Diallo, H. Djidonou, M. Doumbia, G. Enwere, E. S. Higgs, T. Mauget, D. Mory, X. Riveros, F. T. Oumar, A. Toure, A. S. Vicari, I. M. Longini, W. J. Edmunds, A. M. Henao-Restrepo, M. P. Kieny and S. Keita (2017). “Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.” Lancet Infect Dis.
BACKGROUND: In March, 2016, a flare-up of Ebola virus disease was reported in Guinea, and in response ring vaccination with the unlicensed rVSV-ZEBOV vaccine was introduced under expanded access, the first time that an Ebola vaccine has been used in an outbreak setting outside a clinical trial. Here we describe the safety of rVSV-ZEBOV candidate vaccine and operational feasibility of ring vaccination as a reactive strategy in a resource-limited rural setting. METHODS: Approval for expanded access and compassionate use was rapidly sought and obtained from relevant authorities. Vaccination teams and frozen vaccine were flown to the outbreak settings. Rings of contacts and contacts of contacts were defined and eligible individuals, who had given informed consent, were vaccinated and followed up for 21 days under good clinical practice conditions. FINDINGS: Between March 17 and April 21, 2016, 1510 individuals were vaccinated in four rings in Guinea, including 303 individuals aged between 6 years and 17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among the vaccinees. Adverse events following vaccination were reported in 47 (17%) 6-17 year olds (all mild) and 412 (36%) adults (individuals older than 18 years; 98% were mild). Children reported fewer arthralgia events than adults (one [<1%] of 303 children vs 81 [7%] of 1207 adults). No severe vaccine-related adverse events were reported. INTERPRETATION: The results show that a ring vaccination strategy can be rapidly and safely implemented at scale in response to Ebola virus disease outbreaks in rural settings. FUNDING: WHO, Gavi, and the World Food Programme.
HIV- Acute Infection
Sanders, E. J., M. A. Price, E. Karita, A. Kamali, W. Kilembe, L. G. Bekker, S. Lakhi, M. Inambao, O. Anzala, P. E. Fast, J. Gilmour and K. A. Powers (2017). “Differences in acute retroviral syndrome by HIV-1 subtype in a multicentre cohort study in Africa.” AIDS.
BACKGROUND: Symptoms of acute retroviral syndrome (ARS) may be used to identify patients with acute HIV-1 infection who seek care. ARS symptoms in African adults differ by region. We assessed whether reporting of ARS was associated with HIV-1 subtype in a multicentre African cohort study representing countries with predominant HIV-1 subtypes A, C and D. METHODOLOGY: ARS symptoms were assessed in adults enrolling </=6 weeks after the estimated date of infection (EDI) in an acute and early HIV-1 infection cohort study. HIV-1 subtype was determined by POL-genotyping. We used log-binomial regression to compare ARS symptom prevalence among those with subtype A vs. C or D, adjusting for sex, time since enrollment, and enrolment viral load. RESULTS: Among 183 volunteers ascertained </=6 weeks after EDI, 77 (42.0%) had subtype A, 83 (45.4%) subtype C, and 23 (12.6%) subtype D infection. Individuals with subtype A were 1.40 (95% CI: 1.17, 1.68) times as likely as individuals with subtypes C or D to report any ARS symptoms; each individual symptom other than rash was also more prevalent in subtype A than in subtype C or D, with prevalence ratios ranging from 1.94 (1.40, 2.70) for headache to 4.92 (2.24, 10.78) for lymphadenopathy. CONCLUSIONS: Individuals with subtype A were significantly more likely than individuals with subtypes C or D to report any ARS symptoms. HIV-1 subtypes may help explain differences in ARS that have been observed across regions in Africa, and may impact the yield of symptom-based screening strategies for acute HIV infection detection.
HIV – Africa
Koen, J., D. Wassenaar and N. Mamotte (2017). “The ‘over-researched community’: An ethics analysis of stakeholder views at two South African HIV prevention research sites.” Soc Sci Med 194: 1-9.
Health research in resource-limited, multi-cultural contexts raises complex ethical concerns. The term ‘over-researched community’ (ORC) has been raised as an ethical concern and potential barrier to community participation in research. However, the term lacks conceptual clarity and is absent from established ethics guidelines and academic literature. In light of the concern being raised in relation to research in low- and middle-income countries (LMICs), a critical and empirical exploration of the meaning of ORC was undertaken. Guided by Emanuel et al.’s (2004) eight principles for ethically sound research in LMICs, this study examines the relevance and meaning of the terms ‘over-research’ and ‘over-researched community’ through an analysis of key stakeholder perspectives at two South African research sites. Data were collected between August 2007 and October 2008. ‘Over-research’ was found to represent a conglomeration of ethical concerns often used as a proxy for standard research ethics concepts. ‘Over-research’ seemed fundamentally linked to disparate positions and perspectives between different stakeholders in the research interaction, arising from challenges in inter-stakeholder relationships. ‘Over-research’ might be interpreted to mean exploitation. However, exploitation itself could mean different things. Using the term may lead to obscured understanding of real or perceived ethical concerns, making it difficult to identify and address the underlying concerns. It is recommended that the term be carefully and critically interrogated for clarity when used in research ethics discourse. Because it represents other legitimate concerns, it should not be dismissed without careful exploration.
Kiwuwa-Muyingo, S., J. Nazziwa, D. Ssemwanga, P. Ilmonen, H. Njai, N. Ndembi, C. Parry, P. K. Kitandwe, A. Gershim, J. Mpendo, L. Neilsen, J. Seeley, H. Seppala, F. Lyagoba, A. Kamali and P. Kaleebu (2017). “HIV-1 transmission networks in high risk fishing communities on the shores of Lake Victoria in Uganda: A phylogenetic and epidemiological approach.” PLoS One 12(10): e0185818.
BACKGROUND: Fishing communities around Lake Victoria in sub-Saharan Africa have been characterised as a population at high risk of HIV-infection. METHODS: Using data from a cohort of HIV-positive individuals aged 13-49 years, enrolled from 5 fishing communities on Lake Victoria between 2009-2011, we sought to identify factors contributing to the epidemic and to understand the underlying structure of HIV transmission networks. Clinical and socio-demographic data were combined with HIV-1 phylogenetic analyses. HIV-1 gag-p24 and env-gp-41 sub-genomic fragments were amplified and sequenced from 283 HIV-1-infected participants. Phylogenetic clusters with >/=2 highly related sequences were defined as transmission clusters. Logistic regression models were used to determine factors associated with clustering. RESULTS: Altogether, 24% (n = 67/283) of HIV positive individuals with sequences fell within 34 phylogenetically distinct clusters in at least one gene region (either gag or env). Of these, 83% occurred either within households or within community; 8/34 (24%) occurred within household partnerships, and 20/34 (59%) within community. 7/12 couples (58%) within households clustered together. Individuals in clusters with potential recent transmission (11/34) were more likely to be younger 71% (15/21) versus 46% (21/46) in un-clustered individuals and had recently become resident in the community 67% (14/21) vs 48% (22/46). Four of 11 (36%) potential transmission clusters included incident-incident transmissions. Independently, clustering was less likely in HIV subtype D (adjusted Odds Ratio, aOR = 0.51 [95% CI 0.26-1.00]) than A and more likely in those living with an HIV-infected individual in the household (aOR = 6.30 [95% CI 3.40-11.68]). CONCLUSIONS: A large proportion of HIV sexual transmissions occur within house-holds and within communities even in this key mobile population. The findings suggest localized HIV transmissions and hence a potential benefit for the test and treat approach even at a community level, coupled with intensified HIV counselling to identify early infections.
HIV – Cures & Treatments
McGary, C. S., C. Deleage, J. Harper, L. Micci, S. P. Ribeiro, S. Paganini, L. Kuri-Cervantes, C. Benne, E. S. Ryan, R. Balderas, S. Jean, K. Easley, V. Marconi, G. Silvestri, J. D. Estes, R. P. Sekaly and M. Paiardini (2017). “CTLA-4+PD-1- Memory CD4+ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques. “Immunity 47(4): 776-788 e775.
Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1- memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh cells, SIV-enriched CTLA-4+PD-1- CD4+ T cells were found outside the B cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1- memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.
Leibman, R. S., M. W. Richardson, C. T. Ellebrecht, C. R. Maldini, J. A. Glover, A. J. Secreto, I. Kulikovskaya, S. F. Lacey, S. R. Akkina, Y. Yi, F. Shaheen, J. Wang, K. A. Dufendach, M. C. Holmes, R. G. Collman, A. S. Payne and J. L. Riley (2017). “Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor.” PLoS Pathog 13(10): e1006613.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Julg, B. and D. H. Barouch (2017). “HIV-1 Latency by Transition.” Immunity 47(4): 611-612.
The latent HIV-1 reservoir represents the major barrier for the development of an HIV-1 cure. In this issue of Immunity, Shan et al. (2017) highlight that effector-to-memory transitioning (EMT) CD4+ T cells are particularly permissive for the establishment of latent HIV-1 infection.
HIV – Evolution
Dapp, M. J., K. M. Kober, L. Chen, D. H. Westfall, K. Wong, H. Zhao, B. M. Hall, W. Deng, T. Sibley, S. Ghorai, K. Kim, N. Chen, S. McHugh, L. Au, M. Cohen, K. Anastos and J. I. Mullins (2017). “Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.” PLoS One 12(10): e0182443.
Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women’s Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men.
HIV – HLA
Natasja G. de Groot, N. G., C. M. C. Heijmans, A. H. de Ru, G. M. C. Janssen, J. W. Drijfhout, N. Otting, C. Vangenot, G. G. M. Doxiadis, F. Koning, P. A. van Veelen and R. E. Bontrop (2017). “A Specialist Macaque MHC Class I Molecule with HLA-B*27-like Peptide-Binding Characteristics.” J Immunol.
In different macaque species, the MHC A2*05 gene is present in abundance, and its gene products are characterized by low cell-surface expression and a highly conserved peptide-binding cleft. We have characterized the peptide-binding motif of Mamu-A2*05:01, and elucidated the binding capacity for virus-derived peptides. The macaque A2*05 allotype prefers the basic amino acid arginine at the second position of the peptide, and hydrophobic and polar amino acids at the C-terminal end. These preferences are shared with HLA-B*27 and Mamu-B*008, molecules shown to be involved in elite control in human HIV type 1 and macaque SIV infections, respectively. In contrast, however, Mamu-A2*05 preferentially binds 8-mer peptides. Retention in the endoplasmic reticulum seems to be the cause of the lower cell-surface expression. Subsequent peptide-binding studies have illustrated that Mamu-A2*05:01 is able to bind SIV-epitopes known to evoke a strong CD8+ T cell response in the context of the Mamu-B*008 allotype in SIV-infected rhesus macaques. Thus, the macaque A2*05 gene encodes a specialized MHC class I molecule, and is most likely transported to the cell surface only when suitable peptides become available.
HIV – IMMUNE ACTIVATION
Tremblay-McLean, A., J. Bruneau, B. Lebouche, I. Lisovsky, R. Song and N. F. Bernard (2017). “Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4(+) T Cells.” Viruses 9(10).
Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24(+) HIV iCD4s that maintained cell surface CD4 (iCD4(+)), did not maintain CD4 (iCD4-) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4(+) cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4-) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells.
Huot, N., B. Jacquelin, T. Garcia-Tellez, P. Rascle, M. J. Ploquin, Y. Madec, R. K. Reeves, N. Derreudre-Bosquet and M. Muller-Trutwin (2017). “Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys.” Nat Med.
Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.
HIV – Neutralizing Antibodies
Rocha, C., J. Duarte, P. Borrego, R. Calado, J. M. Marcelino, R. Tendeiro, E. Valadas, A. E. Sousa and N. Taveira (2017). “Potency of HIV-2-specific antibodies increase in direct association with loss of memory B-cells.” Aids.
Potent HIV neutralizing antibodies are critical for vaccination and viral reservoir control. High levels of neutralizing antibodies characterize HIV-2 infection, a naturally-occurring model of attenuated HIV disease with low to undectable viremia. We found that HIV-2-specific antibody potency increased in direct association with the loss of both switched and unswitched memory B-cells in untreated HIV-2 infection. Thus, HIV antibody affinity maturation is linked to memory B-cell exhaustion even in reduced viremia settings.
Gama, L. and R. A. Koup (2017). “New-Generation High-Potency and Designer Antibodies: Role in HIV-1 Treatment.” Annu Rev Med.
Broadly neutralizing antibodies (bNAbs) have been evaluated as promising agents in the fight against infectious diseases. HIV-1-specific bNAbs, in particular, have been tested in both preventive and therapeutic modalities. Multiple bNAbs have been isolated, characterized, and assessed in vitro and in vivo, but no single antibody appears to possess the breadth and potency that may be needed if it is to be used in the treatment of HIV-1 infection. With the technological advances of the past decades, novel and more effective bNAbs have been identified or engineered for higher neutralizing potency, greater breadth, and increased serum half-life. In this review, we discuss the development of a new generation of anti-HIV-1 bNAbs and their potential to be used clinically for treatment and prevention of HIV-1 infection. Expected final online publication date for the Annual Review of Medicine Volume 69 is January 29, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
HIV – Prevention Adherence
Husnik, M. J., E. R. Brown, M. Marzinke, E. Livant, T. Palanee-Phillips, C. W. Hendrix, F. Matovu Kiweewa, G. Nair, L. E. Soto-Torres, K. Schwartz, S. L. Hillier and J. M. Baeten (2017). “Implementation of a Novel Adherence Monitoring Strategy in a Phase III, Blinded, Placebo-Controlled, HIV-1 Prevention Clinical Trial.” J Acquir Immune Defic Syndr 76(3): 330-337.
BACKGROUND: Placebo-controlled HIV-1 prevention trials of pre-exposure prophylaxis (PrEP) have not generally used concurrent measurement of adherence because of the potential risk of unblinding. However, several pre-exposure prophylaxis trials for HIV-1 prevention among women failed to show effectiveness because of low product adherence. Evaluation of product adherence objectively during a study provides the opportunity for strengthening adherence activities at sites having low adherence. METHODS: During MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine intravaginal ring, we implemented an adherence monitoring system. Monitoring began in quarter 1 (Q1) 2013 and continued through the conclusion of the trial. Blood plasma was collected quarterly and tested for dapivirine concentrations while maintaining blinding among study team members involved in participant management. Dapivirine concentrations >95 pg/mL, reflecting >8 hours of continuous use, were assessed as signaling product use. Study leadership monitored results on a monthly basis and provided feedback to site investigators. Experiences were shared across sites to motivate staff and counsel participants to strive toward higher adherence levels. RESULTS: An upward trend in adherence was observed (P < 0.0001); the proportion of samples from subjects in the active arm with dapivirine >95 pg/mL increased from 63% in Q1 2013 to 84% by Q1 2015. CONCLUSIONS: Ongoing drug level testing as a marker of adherence in MTN-020/ASPIRE demonstrates the feasibility of real-time adherence monitoring while maintaining study blinding at the level of participants, sites, and study leadership. This approach is novel for large-scale effectiveness studies for HIV-1 prevention.
Cossarizza, A., H. D. Chang, A. Radbruch, I. Andra, F. Annunziato, P. Bacher, V. Barnaba, L. Battistini, W. M. Bauer, S. Baumgart, B. Becher, W. Beisker, C. Berek, A. Blanco, G. Borsellino, P. E. Boulais, R. R. Brinkman, M. Buscher, D. H. Busch, T. P. Bushnell, X. Cao, A. Cavani, P. K. Chattopadhyay, Q. Cheng, S. Chow, M. Clerici, A. Cooke, A. Cosma, L. Cosmi, A. Cumano, V. D. Dang, D. Davies, S. De Biasi, G. Del Zotto, S. Della Bella, P. Dellabona, G. Deniz, M. Dessing, A. Diefenbach, J. Di Santo, F. Dieli, A. Dolf, V. S. Donnenberg, T. Dorner, G. R. A. Ehrhardt, E. Endl, P. Engel, B. Engelhardt, C. Esser, B. Everts, C. S. Falk, T. A. Fehniger, A. Filby, S. Fillatreau, M. Follo, I. Forster, J. Foster, G. A. Foulds, P. S. Frenette, D. Galbraith, N. Garbi, M. D. Garcia-Godoy, K. Ghoreschi, L. Gibellini, C. Goettlinger, C. S. Goodyear, A. Gori, J. Grogan, M. Gross, A. Grutzkau, D. Grummitt, J. Hahn, Q. Hammer, A. E. Hauser, D. L. Haviland, D. Hedley, G. Herrera, M. Herrmann, F. Hiepe, T. Holland, P. Hombrink, J. P. Houston, B. F. Hoyer, B. Huang, C. A. Hunter, A. Iannone, H. M. Jack, B. Javega, S. Jonjic, K. Juelke, S. Jung, T. Kaiser, T. Kalina, B. Keller, S. Khan, D. Kienhofer, T. Kroneis, D. Kunkel, C. Kurts, P. Kvistborg, J. Lannigan, O. Lantz, A. Larbi, S. LeibundGut-Landmann, M. D. Leipold, M. K. Levings, V. Litwin, Y. Liu, M. Lohoff, G. Lombardi, L. Lopez, A. Lovett-Racke, E. Lubberts, B. Ludewig, E. Lugli, H. T. Maecker, G. Martrus, G. Matarese, C. Maueroder, M. McGrath, I. McInnes, H. E. Mei, F. Melchers, S. Melzer, D. Mielenz, K. Mills, J. Mjosberg, J. Moore, B. Moran, A. Moretta, L. Moretta, T. R. Mosmann, S. Muller, W. Muller, C. Munz, G. Multhoff, L. E. Munoz, K. M. Murphy, T. Nakayama, M. Nasi, C. Neudorfl, J. Nolan, S. Nourshargh, J. E. O’Connor, W. Ouyang, A. Oxenius, R. Palankar, I. Panse, P. Peterson, C. Peth, J. Petriz, D. Philips, W. Pickl, S. Piconese, M. Pinti, A. G. Pockley, M. J. Podolska, C. Pucillo, S. A. Quataert, T. Radstake, B. Rajwa, J. A. Rebhahn, D. Recktenwald, E. B. M. Remmerswaal, K. Rezvani, L. G. Rico, J. P. Robinson, C. Romagnani, A. Rubartelli, J. Ruland, S. Sakaguchi, F. Sala-de-Oyanguren, Y. Samstag, S. Sanderson, B. Sawitzki, A. Scheffold, M. Schiemann, F. Schildberg, E. Schimisky, S. A. Schmid, S. Schmitt, K. Schober, T. Schuler, A. R. Schulz, T. Schumacher, C. Scotta, T. V. Shankey, A. Shemer, A. K. Simon, J. Spidlen, A. M. Stall, R. Stark, C. Stehle, M. Stein, T. Steinmetz, H. Stockinger, Y. Takahama, A. Tarnok, Z. Tian, G. Toldi, J. Tornack, E. Traggiai, J. Trotter, H. Ulrich, M. van der Braber, R. A. W. van Lier, M. Veldhoen, S. Vento-Asturias, P. Vieira, D. Voehringer, H. D. Volk, K. von Volkmann, A. Waisman, R. Walker, M. D. Ward, K. Warnatz, S. Warth, J. V. Watson, C. Watzl, L. Wegener, A. Wiedemann, J. Wienands, G. Willimsky, J. Wing, P. Wurst, L. Yu, A. Yue, Q. Zhang, Y. Zhao, S. Ziegler and J. Zimmermann (2017). “Guidelines for the use of flow cytometry and cell sorting in immunological studies.” Eur J Immunol 47(10): 1584-1797.
Li, M., Y. Li, K. Peng, Y. Wang, T. Gong, Z. Zhang, Q. He and X. Sun (2017). “Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses.” Acta Biomater.
Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. SIGNIFICANCE: As we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
Vaccine Design Immunogenicity Efficacy
Shen, C., J. Chen, R. Li, M. Zhang, G. Wang, S. Stegalkina, L. Zhang, J. Chen, J. Cao, X. Bi, S. F. Anderson, T. Alefantis, M. Zhang, X. Cai, K. Yang, Q. Zheng, M. Fang, H. Yu, W. Luo, Z. Zheng, Q. Yuan, J. Zhang, J. Wai-Kuo Shih, H. Kleanthous, H. Chen, Y. Chen and N. Xia (2017). “A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses.” Science Translational Medicine 9(412).
Although it circulates globally and is prevalent enough to warrant inclusion in the seasonal influenza vaccine, influenza B is far less well studied than its cousin, influenza A, and therapeutics are lacking. Shen et al. have now generated a potent antibody that inhibits diverse strains of influenza B virus. The antibody recognizes the receptor binding site in hemagglutinin, a region critical to viral entry, and was shown to be therapeutically effective in mice and ferrets. This antibody could be widely deployed to treat or prevent influenza B infection around the world. Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages. Notably, C12G6 exhibits broad cross-lineage hemagglutination inhibition activity against influenza B viruses and has higher potency and breadth of neutralization when compared to four previously reported influenza B bnAbs. In vivo, C12G6 confers stronger cross-protection against Yamagata and Victoria lineages of influenza B viruses in mice and ferrets than other bnAbs or the anti-influenza drug oseltamivir and has an additive antiviral effect when administered in combination with oseltamivir. Epitope mapping indicated that C12G6 targets a conserved epitope that overlaps with the receptor binding site in the HA region of influenza B virus, indicating why it neutralizes virus so potently. Mechanistic analyses revealed that C12G6 inhibits influenza B viruses via multiple mechanisms, including preventing viral entry, egress, and HA-mediated membrane fusion and triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity responses. C12G6 is therefore a promising candidate for the development of prophylactics or therapeutics against influenza B infection and may inform the design of a truly universal influenza vaccine
Belongia, E. (2017). “Beyond Antigenic Match: Moving Toward Greater Understanding of Influenza Vaccine Effectiveness.” J Infect Dis.
Bull, J. J., M. W. Smithson and S. L. Nuismer (2017). “Transmissible Viral Vaccines.” Trends Microbiol.
Genetic engineering now enables the design of live viral vaccines that are potentially transmissible. Some designs merely modify a single viral genome to improve on the age-old method of attenuation whereas other designs create chimeras of viral genomes. Transmission has the benefit of increasing herd immunity above that achieved by direct vaccination alone but also increases the opportunity for vaccine evolution, which typically undermines vaccine utility. Different designs have different epidemiological consequences but also experience different evolution. Approaches that integrate vaccine engineering with an understanding of evolution and epidemiology will reap the greatest benefit from vaccine transmission.
Chromikova, V., M. A. Zaragoza and F. Krammer (2017). “Generation of a serum free CHO DG44 cell line stably producing a broadly protective anti-influenza virus monoclonal antibody.”PLoS One 12(9): e0183315.
Because of the broad neutralization and in vivo protection across influenza A and influenza B virus strains, monoclonal antibody CR9114 is widely used in influenza virus research as a positive control in many experiments. To produce amounts sufficient for the demand requires regular transient transfections, resulting in varying yield as well as differing batch to batch quality. Here, we report the development of a serum-free CHO DG44 cell line, stably producing a CR9114-like antibody with a potential to become a useful influenza virus research tool.
Ortiz, J. R. (2017). “The challenge of vaccine policy-making with imperfect data.” Clin Infect Dis.
Rappuoli, R., E. Siena and O. Finco (2017). “Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Systems Biology Views of Vaccine Innate and Adaptive Immunity.” Cold Spring Harb Perspect Biol.
During the last decade, several high-throughput technologies have been applied to gather deeper understanding on the biological events elicited by vaccination. The main goal of systems biology is to integrate different sources of data and extract biologically meaningful information. This holistic approach has provided new insights on the impact that the innate immune status has on vaccine responsiveness. Other factors like chronic infections, age, microbiome, and metabolism can influence the outcome of vaccination, and systems biology offers unique opportunities to expand our understanding of their role on the immune response. However, a few challenges that still need to be overcome will be discussed.
Hosangadi, D., P. G. Smith and B. K. Giersing (2017). “Considerations for using ETEC and Shigella disease burden estimates to guide vaccine development strategy.” Vaccine.
Enterotoxigenic E. coli (ETEC) and Shigella are enteropathogens causing significant global morbidity and mortality, particularly in low-income countries. No licensed vaccine exists for either pathogen, but candidates are in development, with the most advanced candidates potentially approaching pivotal efficacy testing within the next few years. A positive policy recommendation for introduction of any vaccine, following licensure, depends on evidence of vaccine cost-effectiveness and impact on morbidity and mortality. The mortality estimates for these two pathogens have fluctuated over recent years, which has led to uncertainty in the assessment of their relative public health importance for use in low and middle-income countries. This paper summarizes the various ETEC and Shigella disease burden estimates, based on a review of current literature and informal consultations with leading stakeholders in enteric disease modelling. We discuss the factors that underpin the variability, including differences in the modelling methodology; diagnostic tools used to ascertain diarrheal etiology; epidemiological setting; the data that are available to incorporate; and absolute changes in the total number of diarrheal deaths over time. We consider the further work that will strengthen the evidence needed to support future decision making with respect to recommendations on the relative utility of these vaccines.
Davis, M. M. and C. M. Tato (2017). “Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Seeing the Forest Rather than a Few Trees.” Cold Spring Harb Perspect Biol.
Preventing morbidity and mortality from infectious disease through the development and use of effective vaccines is one of medicine’s greatest achievements and greatest frustrations. We are struggling with improving vaccine efficacy for some of the most globally widespread diseases, such as malaria and tuberculosis. In an effort to gain an edge, systems biology approaches have begun to be employed to more broadly investigate the pathways leading to protective vaccine responses. As such, we are now at a critical juncture, needing to evaluate how fruitful these approaches have been. Herein we discuss the level of success achieved as compared to the original promise of systems methodologies, and conclude that while we have indeed begun to make clear inroads into understanding the immune response to vaccines, we still have much to learn and gain from the more comprehensive approach of systems-level analysis.
Hagan, T. and B. Pulendran (2017). “Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? From Data to Understanding through Systems Biology.” Cold Spring Harb Perspect Biol.
The advent of high-throughput “omics” technologies, combined with the computational and statistical methods necessary to analyze such data, have revolutionized biology, enabling a global view of the complex molecular processes and interactions that occur within a biological system. Such systems-based approaches have begun to be used in the evaluation of immune responses to vaccination, with the promise of identifying predictive biomarkers capable of rapidly evaluating vaccine efficacy, transforming our understanding of the immune mechanisms responsible for protective responses to vaccination and contributing to a new generation of rationally designed vaccines. Here we present our opinion that systems biology does indeed have a critical role in the future of vaccinology. Such approaches have shown potential in identifying transcriptional and cellular signatures of responsiveness to vaccination using diverse vaccines, adjuvants, and human populations. These findings, coupled with further mechanistic evaluation in animal models, will guide development of targeted vaccine and adjuvant formulations designed to optimally induce protective responses in populations of differing immune status.
Frey, S. E., K. Lottenbach, I. Graham, E. Anderson, K. Bajwa, R. C. May, S. B. Mizel, A. Graff and R. B. Belshe (2017). “A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).” Vaccine.
INTRODUCTION: Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. METHODS: We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject’s participation lasted 13months. RESULTS: Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. CONCLUSION: The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited.
Friedman, H., N. Ator, N. Haigwood, W. Newsome, J. S. Allan, T. G. Golos, J. H. Kordower, R. E. Shade, M. E. Goldberg, M. R. Bailey and P. Bianchi (2017). “THE CRITICAL ROLE OF NONHUMAN PRIMATES IN MEDICAL RESEARCH.” Pathog Immun 2(3): 352-365.
Germain, R. N. (2017). “Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? What Really Constitutes the Study of “Systems Biology” and How Might Such an Approach Facilitate Vaccine Design.” Cold Spring Harb Perspect Biol.
A dichotomy exists in the field of vaccinology about the promise versus the hype associated with application of “systems biology” approaches to rational vaccine design. Some feel it is the only way to efficiently uncover currently unknown parameters controlling desired immune responses or discover what elements actually mediate these responses. Others feel that traditional experimental, often reductionist, methods for incrementally unraveling complex biology provide a more solid way forward, and that “systems” approaches are costly ways to collect data without gaining true insight. Here I argue that both views are inaccurate. This is largely because of confusion about what can be gained from classical experimentation versus statistical analysis of large data sets (bioinformatics) versus methods that quantitatively explain emergent properties of complex assemblies of biological components, with the latter reflecting what was previously called “physiology.” Reductionist studies will remain essential for generating detailed insight into the functional attributes of specific elements of biological systems, but such analyses lack the power to provide a quantitative and predictive understanding of global system behavior. But by employing (1) large-scale screening methods for discovery of unknown components and connections in the immune system (omics), (2) statistical analysis of large data sets (bioinformatics), and (3) the capacity of quantitative computational methods to translate these individual components and connections into models of emergent behavior (systems biology), we will be able to better understand how the overall immune system functions and to determine with greater precision how to manipulate it to produce desired protective responses.