AIDS Vaccine Design Immunogenicity Efficacy
Wijesundara, D. K., C. Ranasinghe, B. Grubor-Bauk and E. J. Gowans (2017). “Emerging Targets for Developing T Cell-Mediated Vaccines for Human Immunodeficiency Virus (HIV)-1.” Front Microbiol 8: 2091.
Human immunodeficiency virus (HIV)-1 has infected >75 million individuals globally, and, according to the UN, is responsible for ~2.1 million new infections and 1.1 million deaths each year. Currently, there are ~37 million individuals with HIV infection and the epidemic has already resulted in 35 million deaths. Despite the advances of anti-retroviral therapy (ART), a cost-effective vaccine remains the best long-term solution to end the HIV-1 epidemic especially given that the vast majority of infected individuals live in poor socio-economic regions of the world such as Sub-Saharan Africa which limits their accessibility to ART. The modest efficacy of the RV144 Thai trial provides hope that a vaccine for HIV-1 is possible, but as markers for sterilizing immunity are unknown, the design of an effective vaccine is empirical, although broadly cross-reactive neutralizing antibodies (bNAb) that can neutralize various quasispecies of HIV-1 are considered crucial. Since HIV-1 transmission often occurs at the genito-rectal mucosa and is cell-associated, there is a need to develop vaccines that can elicit CD8+ T cell immunity with the capacity to kill virus infected cells at the genito-rectal mucosa and the gut. Here we discuss the recent progress made in developing T cell-mediated vaccines for HIV-1 and emphasize the need to elicit mucosal tissue-resident memory CD8+ T (CD8+ Trm) cells. CD8+ Trm cells will likely form a robust front-line defense against HIV-1 and eliminate transmitter/founder virus-infected cells which are responsible for propagating HIV-1 infections following transmission in vast majority of cases.
Emerging Infectious Diseases
Allegranzi, B., C. Kilpatrick, J. Storr, E. Kelley, B. J. Park, L. Donaldson, P. Global Infection and N. Control (2017). “Global infection prevention and control priorities 2018-22: a call for action.” Lancet Glob Health 5(12): e1178-e1180.
Paules, C. I., R. W. Eisinger, H. D. Marston and A. S. Fauci (2017). “What Recent History Has Taught Us About Responding to Emerging Infectious Disease Threats.” Ann Intern Med.
Presidential administrations face any number of unexpected crises during their tenure, and global pandemics are among the most challenging. As of January 2017, one of the authors had served under 5 presidents as the director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. During each administration, the government faced unexpected pandemics, ranging from the HIV/AIDS pandemic, which began during the Reagan administration, to the recent Zika outbreak in the Americas, which started during the Obama administration. These experiences underscored the need to optimize preparation for and response to these threats whenever and wherever they emerge. This article recounts selected outbreaks occurring during this period and highlights lessons that were learned that can be applied to the infectious disease threats that will inevitably be faced in the current presidential administration and beyond.
Emerging Infectious Diseases Vaccines
Cashman, K. A., E. R. Wilkinson, S. E. Wollen, J. D. Shamblin, J. M. Zelko, J. J. Bearss, X. Zeng, K. E. Broderick and C. S. Schmaljohn (2017). “DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs.” Hum Vaccin Immunother: 0.
We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 microg of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinates succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed-infection environment.
Feinberg, M. B. and R. Ahmed (2017). “Advancing dengue vaccine development.” Science 358(6365): 865-866.
Dengue virus (DENV) is a member of the viral genus Flavivirus, which also includes yellow fever virus (YFV) and Zika virus (ZIKV). DENV infection is a major and growing global health threat: There are ∼400 million cases of infection, ∼500,000 hospitalizations, and ∼12,500 deaths now estimated to occur each year (1). Dengue represents the most common mosquito-borne disease in humans (1). A remarkable 50% of the world’s population now lives in regions where DENV transmission is manifest. Dengue is associated with a wide spectrum of clinical outcomes, ranging from mild febrile illnesses to dengue hemorrhagic fever to the most severe clinical presentation of dengue shock syndrome, which is characterized by profound systemic cytokine activation, vascular leakage, and shock—this carries a high risk of death. On page 929 of this issue, Katzelnick et al. (2) analyzed DENV infection outcome data gleaned from the long-term followup of a cohort of Nicaraguan children (2). They found that the risk of severe dengue disease upon subsequent DENV infection correlated with baseline DENV antibody concentrations (titers), which has implications for DENV vaccination approaches.
Plotkin, S. A. (2017). “Vaccines We Need But Don’t Have.” Viral Immunol.
Vaccinations have had tremendous success in the 20th century. However, in the 21st century, we are facing complex immunological issues in relation to controlling underlying infectious diseases. Therefore, new technologies are needed to develop vaccines against infectious diseases like respiratory syncytial virus, human immunodeficiency virus, and cytomegalovirus. In addition, recent emerging infections have taught us that we must prepare preventative measures in advance using our scientific abilities.
HIV – Africa
African scientists get their own open-access publishing platform. Nature 15 November 2017
Africa’s academy of science has announced that it will launch an open-access publishing platform early next year — the first of its kind aimed exclusively at scientists on the continent. The platform, called AAS Open Research and announced by the African Academy of Sciences (AAS) in Nairobi on 15 November, is being created with the London-based open-access publisher F1000, adopting the model of its F1000Research publishing platform. AAS Open Research will publish articles, research protocols, data sets and code, usually within days of submission and before peer review. F1000 staff will arrange post-publication peer review: the reviews and the names of their authors will be published alongside the papers. The papers will be indexed in abstract databases such as PubMed only after they pass review.
(2017). “Evidence for HIV Prevention in Southern Africa (EHPSA).” Afr J AIDS Res 16(4): iv.
Awad, S. F., H. Chemaitelly and L. J. Abu-Raddad (2017). “Estimating the annual risk of HIV transmission within HIV sero-discordant couples in sub-Saharan Africa.” Int J Infect Dis.
OBJECTIVE: To estimate the annual risk of HIV transmission (varphi) within HIV sero-discordant couples in 23 countries in sub-Saharan Africa (SSA), by utilizing newly-available national population-based data and accounting for factors known to potentially affect this estimation. METHODS: We used a recently-developed pair-based mathematical model that accommodates for HIV-dynamics temporal variation, sexual risk-behavior heterogeneity, and antiretroviral therapy (ART) scale-up. RESULTS: Estimated country-specific varphi (in absence of ART) ranged between 4.2% (95% uncertainty interval (UI): 1.9%-6.3%) and 47.4% (95% UI: 37.2%-69.0%) per person-year (ppy), with a median of 12.4%. varphi was strongly associated with HIV prevalence, with a Pearson correlation coefficient of 0.92, and was larger in high- versus low-HIV-prevalence countries. varphi increased by 1.31% (95% confidence interval: 1.00%-1.55%) ppy for every 1% increase in HIV prevalence. CONCLUSIONS: varphi estimates were similar to earlier estimates, and suggested considerable heterogeneity in HIV infectiousness across SSA. This heterogeneity may explain, partly, the differences in epidemic scales.
Sithole, B. (2017). “HIV prevention needs for men who have sex with men in Swaziland.” Afr J AIDS Res 16(4): 315-320.
Men who have sex with men (MSM) have a high HIV burden and also often face multiple other challenges accessing HIV services, including legal and social issues. Although Swaziland recently started responding with interventions for MSM, significant gaps still exist both in information and programming. This study aimed to explore the HIV prevention needs of MSM in Swaziland, including factors elevating their risks and vulnerabilities to HIV infection; to find out what HIV prevention strategies exist; and to determine how best to meet the prevention needs of MSM. A total of 50 men who reported anal sex with other men in the past 12 months were recruited through simple respondent driven sampling. They completed either a structured quantitative survey (n = 35) or participated in a semi-structured qualitative interview (n = 15). Both quantitative and qualitative findings indicated perceived and experienced stigma among MSM. This predominantly manifested as internalised stigma, which may lead to alcohol abuse and sexual risky behaviours. At least 83% (29/35) of the quantitative sample had been labelled with derogatory terms because of their sexual orientation, while 66% (23/35) had experienced being avoided. There was limited knowledge of risk practices: When asked, 54% (19/35) of quantitative respondents reported that vaginal and anal sex carry an equal risk of HIV infection. Participants also had little knowledge on new HIV prevention methods such as pre-exposure prophylaxis (PrEP) and rectal microbicides. MSM needs included safe spaces in form of drop-in centres and non-hostile HIV services. Although Swaziland recently started interventions for key populations, including MSM, there is still a general lack on information to inform managers and implementers on the HIV prevention needs of MSM in Swaziland. Such information is crucial for designers of official and HIV programmes. Research is needed to increase knowledge on the HIV prevention needs for key populations, including MSM.
El-Sadr, W. M., M. Rabkin, J. Nkengasong and D. L. Birx (2017). “Realizing the potential of routine viral load testing in sub-Saharan Africa.” J Int AIDS Soc 20 Suppl 7: 1-3.
Lundgren, J. (2017). “Quantification of sexual HIV transmission risk in Africa.” Int J Infect Dis.
Mabuza, K. and T. Dlamini (2017). “History of the HIV epidemic and response in Swaziland.” Afr J AIDS Res 16(4): v-ix.
Mayanja, Y., O. Kamacooko, D. Bagiire, G. Namale, P. Kaleebu and J. Seeley (2017). “‘Test and Treat’ Among Women at High Risk for HIV-infection in Kampala, Uganda: Antiretroviral Therapy Initiation and Associated Factors.” AIDS Behav.
Data on implementation of ‘Test and Treat’ among key populations in sub-Saharan Africa are still limited. We examined factors associated with prompt antiretroviral therapy/ART (within 1 month of HIV-positive diagnosis or 1 week if pregnant) among 343 women at high risk for HIV infection in Kampala-Uganda, of whom 28% initiated prompt ART. Most (95%) reported paid sex within 3 months prior to enrolment. Multivariable logistic regression was used to determine baseline characteristics associated with prompt ART. Sex work as main job, younger age and being widowed/separated were associated with lower odds of prompt ART; being enrolled after 12 months of implementing the intervention was associated with higher odds of prompt ART. Younger women, widowed/separated and those reporting sex work as their main job need targeted interventions to start ART promptly after testing. Staff supervision and mentoring may need strengthening during the first year of implementing ‘test and treat’ interventions.
HIV – Cures & Treatments
Chomont, N., A. A. Okoye, D. Favre and L. Trautmann (2017). “Wake me up before you go: A strategy to reduce the latent HIV reservoir.” Aids.
In the quest to eliminate or reduce the HIV reservoir, shock and kill strategies require the combined administration of a latency reversing agent (LRA) to reactivate the latent reservoir and an intervention to boost effector functions to clear this reservoir. Both parts of this strategy are quite inefficient when LRAs are administered to HIV-infected individuals on suppressive ART for several years, possibly due to low levels of induced antigen expression, negative impact of LRAs on clearance mechanisms, and very low number of effective cytotoxic T cells (CTLs). Here we provide rationale for an approach that would require only the administration of an LRA at the time of ART initiation to significantly reduce the HIV reservoir. The advantage of this strategy is an efficient reactivation of the latent HIV reservoir when high numbers of HIV-specific CD8 T cells are present. This strategy may also potentiate more effective CTL responses and the establishment of a longer period of immune surveillance. This “window of opportunity” has been validated in silico, can be tested in preclinical non-human primate (NHP) models and translated rapidly in the clinic.
Christensen-Quick, A., C. Vanpouille, A. Lisco and S. Gianella (2017). “Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire.” AIDS Res Hum Retroviruses33(S1): S23-s30.
The inherent stability of a small population of T cells that are latently infected with HIV despite antiretroviral therapy (ART) remains a stubborn obstacle to an HIV cure. By exploiting the memory compartment of our immune system, HIV maintains persistence in a small subset of quiescent cells with varying phenotypes, thus evading immune surveillance and clinical detection. Understanding the molecular and immunological mechanisms that maintain the latent reservoir will be critical to the success of HIV eradication strategies. Human cytomegalovirus (CMV), another chronic viral infection, frequently co-occurs with HIV and occupies an oversized proportion of memory T cell responses. CMV and HIV have both evolved complex strategies to manipulate our immune system for their own advantage. Given the increasingly clear links between CMV replication, chronic immune activation, and increased HIV reservoirs, we present a closer examination of the interplay between these two chronic coinfections. Here we review the effects of CMV on the immune system and show how they may affect persistence of the latent HIV reservoir during ART. The studies described herein suggest that hijacking of cytokine and chemokine signaling, manipulation of cell development pathways, and transactivation of HIV expression by CMV might be pouring gas on the fire of HIV persistence. Future interventional studies are required to formally determine the extent to which CMV is causally associated with inflammation and HIV reservoir expansion.
Kiniry, B. E., S. Li, A. Ganesh, P. W. Hunt, M. Somsouk, P. J. Skinner, S. G. Deeks and B. L. Shacklett (2017). “Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection.” Mucosal Immunol.
Tissue-resident memory (TRM) CD8+ T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. Human immunodeficiency virus-1 (HIV-1) is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8+ TRM cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8+ TRM cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8+ T-cells were CD69+CD103+S1PR1- and T-betLowEomesoderminNeg, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8+ TRM responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8+ TRM subsets, distinguished by CD103 expression intensity, were identified. CD103Low CD8+ TRM primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103High CD8+ TRM primarily displayed an effector memory phenotype and were EomesoderminNeg. These findings suggest a large fraction of CD8+ T-cells housed in the human rectosigmoid mucosa are tissue-resident and that TRM contribute to the anti-HIV-1 immune response. Further exploration of CD8+ TRM will inform development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa. Mucosal Immunology advance online publication 15 November 2017; doi:10.1038/mi.2017.96.
Koay, W. L. A., L. V. Siems and D. Persaud (2017). “The microbiome and HIV persistence: implications for viral remission and cure.” Curr Opin HIV AIDS.
PURPOSE OF REVIEW: This article discusses the interaction between HIV infection, the gut microbiome, inflammation and immune activation, and HIV reservoirs, along with interventions to target the microbiome and their implications for HIV remission and cure. RECENT FINDINGS: Most studies show that HIV-infected adults have a gut microbiome associated with decreased bacterial richness and diversity, and associated systemic inflammation and immune activation. A unique set of individuals, elite controllers, who spontaneously control HIV replication, have a similar microbiome to HIV-uninfected individuals. Conversely, exposure to maternal HIV in infants was shown to alter the gut microbiome, even in infants who escaped perinatal infection. Emerging research highlights the importance of the metabolomics and metaproteomics of the gut microbiome, which may have relevance for HIV remission and cure. Together, these studies illustrate the complexity of the relationship between HIV infection, the gut microbiome, and its systemic effects. SUMMARY: Understanding the association of HIV with the microbiome, metabolome, and metaproteome may lead to novel therapies to decrease inflammation and immune activation, and impact HIV reservoir size and vaccine responses. Further research in this area is important to inform HIV remission and cure treatments.
HIV – IMMUNE ACTIVATION
Alaoui, L., G. Palomino, S. Zurawski, G. Zurawski, S. Coindre, N. Dereuddre-Bosquet, C. Lecuroux, C. Goujard, B. Vaslin, C. Bourgeois, P. Roques, R. Le Grand, O. Lambotte and B. Favier (2017). “Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs.” Cell Mol Life Sci.
Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.
HIV – IMMUNE ACTIVATION
Mayer, K. H., K. E. Seaton, Y. Huang, N. Grunenberg, A. Isaacs, M. Allen, J. E. Ledgerwood, I. Frank, M. E. Sobieszczyk, L. R. Baden, B. Rodriguez, H. Van Tieu, G. D. Tomaras, A. Deal, D. Goodman, R. T. Bailer, G. Ferrari, R. Jensen, J. Hural, B. S. Graham, J. R. Mascola, L. Corey and D. C. Montefiori (2017). “Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial.” PLoS Med 14(11): e1002435.
BACKGROUND: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. METHODS AND FINDINGS: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 mug/ml (95% CI: 1,033, 1,340) and 420 mug/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 mug/ml (95% CI: 10, 27) and 6 mug/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 mug/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. CONCLUSIONS: VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants’ sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. TRIAL REGISTRATION: Clinical Trials Registration: NCT02165267.
Morris, L. and N. N. Mkhize (2017). “Prospects for passive immunity to prevent HIV infection.” PLoS Med 14(11): e1002436.
In a Perspective, Lynn Morris and Nonhlanhla Mkhize discuss the prospects for broadly neutralizing antibodies to be used in preventing HIV infection.
Vaccine Design Immunogenicity Efficacy
Ghassemi, S. and B. M. Carreno (2017). “Heating up cancer vaccines.” Sci Immunol 2(17).
A microneedle patch containing melanin promotes systemic antitumor response upon photothermal irradiation.
Ghiasi, H. (2017). “Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth?” J Virol 91(23).
Royer, D. J. and D. J. J. Carr (2017). “Reply to “Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth?”.” J Virol91(23).
Liu, L., D. Wei, Z. Qu, L. Sun, Y. Miao, Y. Yang, J. Lu, W. Du, B. Wang and B. Li (2017). “A safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques.” J Appl Toxicol.
Plague has led to millions of deaths in history and outbreaks continue to the present day. The efficacy limitations and safety concerns of the existing killed whole cell and live-attenuated vaccines call for the development of new vaccines. In this study, we evaluated the immunogenicity and safety of a novel subunit plague vaccine, comprising native F1 antigen and recombinant V antigen. The cynomolgus macaques in low- and high-dose vaccine groups were vaccinated at weeks 0, 2, 4 and 6, at dose levels of 15 mug F1 + 15 mug rV and 30 mug F1 + 30 mug rV respectively. Specific antibodies and interferon-gamma and interleukin-2 expression in lymphocytes were measured. For safety, except for the general toxicity and local irritation, we made a systematic immunotoxicity study on the vaccine including immunostimulation, autoimmunity and anaphylactic reaction. The vaccine induced high levels of serum anti-F1 and anti-rV antibodies, and caused small increases of interferon-gamma and interleukin-2 in monkeys. The vaccination led to a reversible increase in the number of peripheral blood eosinophils, the increases in serum IgE level in a few animals and histopathological change of granulomas at injection sites. The vaccine had no impact on general conditions, most clinical pathology parameters, percentages of T-cell subsets, organ weights and gross pathology of treated monkeys and had passable local tolerance. The F1 + rV subunit plague vaccine can induce very strong humoral immunity and low level of cellular immunity in cynomolgus macaques and has a good safety profile.
Raslan, R., S. El Sayegh, S. Chams, N. Chams, A. Leone and I. Hajj Hussein (2017). “Re-Emerging Vaccine-Preventable Diseases in War-Affected Peoples of the Eastern Mediterranean Region-An Update.” Front Public Health 5: 283.
For the past few decades, the Eastern Mediterranean Region has been one area of the world profoundly shaped by war and political instability. On-going conflict and destruction have left the region struggling with innumerable health concerns that have claimed the lives of many. Wars, and the chaos they leave behind, often provide the optimal conditions for the growth and re-emergence of communicable diseases. In this article, we highlight a few of the major re-emerging vaccine preventable diseases in four countries of the Eastern Mediterranean Region that are currently affected by war leading to a migration crisis: Iraq, South Sudan, Syria, and Yemen. We will also describe the impact these infections have had on patients, societies, and national health care services. This article also describes the efforts, both local and international, which have been made to address these crises, as well as future endeavors that can be done to contain and control further devastation left by these diseases.
Oldham, R. A. A. and J. A. Medin (2017). “Practical considerations for chimeric antigen receptor design and delivery.” Expert Opin Biol Ther 17(8): 961-978.
INTRODUCTION: The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized. Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells. Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects such as improving the safety profile and the anti-tumor potency of CARs, will be required to bring this therapy from early-phase clinical trials to standard of care as an effective treatment for a broad range of tumor types.
Vaccine Design – Vectors
Verna, A. E., V. Franceschi, G. Tebaldi, F. Macchi, V. Menozzi, C. Pastori, L. Lopalco, S. Ottonello, S. Cavirani and G. Donofrio (2017). “Induction of Antihuman C-C Chemokine Receptor Type 5 Antibodies by a Bovine Herpesvirus Type-4 Based Vector.” Front Immunol 8: 1402.
Bovine herpesvirus 4 (BoHV-4) is a promising vector for the delivery and intracellular expression of recombinant antigens and can thus be considered as a new prototype vaccine formulation system. An interesting, and actively pursued, antigen in the context of human immunodeficiency virus (HIV) infection prophylaxis (and therapy) is the C-C chemokine receptor type 5 (CCR5) co-receptor, whose blockage by specific antibodies has been shown to inhibit both viral entry and cell-to-cell transmission of the virus. Building on our previous work on the BoHV-4 vector system, we have engineered and tested a replication-competent derivative of BoHV-4 (BoHV-4-CMV-hCCR5DeltaTK) bearing a human CCR5 (hCCR5) expression cassette. We show here that CCR5 is indeed expressed at high levels in multiple types of BoHV-4-CMV-hCCR5DeltaTK-infected cells. More importantly, two intravenous inoculations of CCR5-expressing BoHV-4 virions into rabbits led to the production of anti-CCR5 antibodies capable of reacting with the CCR5 receptor exposed on the surface of HEK293T cells through specific recognition of the amino-terminal region (aa 14-34) of the protein. Given the growing interest for anti-CCR5 immunization as an HIV control strategy and the many advantages of virus-based immunogen formulations (especially for poorly immunogenic or self-antigens), the results reported in this study provide preliminary validation of BoHV-4 as a safe viral vector suitable for CCR5 vaccination.