• 40 years of the human T-cell leukemia virus: past, present, and future

      Tagaya, Y.; Matsuoka, M.; Gallo, R. (F1000 Research Ltd., 2019)
      It has been nearly 40 years since human T-cell leukemia virus-1 (HTLV-1), the first oncogenic retrovirus in humans and the first demonstrable cause of cancer by an infectious agent, was discovered. Studies indicate that HTLV-1 is arguably one of the most carcinogenic agents to humans. In addition, HTLV-1 causes a diverse array of diseases, including myelopathy and immunodeficiency, which cause morbidity and mortality to many people in the world, including the indigenous population in Australia, a fact that was emphasized only recently. HTLV-1 can be transmitted by infected lymphocytes, from mother to child via breast feeding, by sex, by blood transfusion, and by organ transplant. Therefore, the prevention of HTLV-1 infection is possible but such action has been taken in only a limited part of the world. However, until now it has not been listed by the World Health Organization as a sexually transmitted organism nor, oddly, recognized as an oncogenic virus by the recent list of the National Cancer Institute/National Institutes of Health. Such underestimation of HTLV-1 by health agencies has led to a remarkable lack of funding supporting research and development of treatments and vaccines, causing HTLV-1 to remain a global threat. Nonetheless, there are emerging novel therapeutic and prevention strategies which will help people who have diseases caused by HTLV-1. In this review, we present a brief historic overview of the key events in HTLV-1 research, including its pivotal role in generating ideas of a retrovirus cause of AIDS and in several essential technologies applicable to the discovery of HIV and the unraveling of its genes and their function. This is followed by the status of HTLV-1 research and the preventive and therapeutic developments of today. We also discuss pending issues and remaining challenges to enable the eradication of HTLV-1 in the future.
    • Consensus Report on Shigella Controlled Human Infection Model: Immunological Assays

      Kaminski, R.W.; Pasetti, M.F.; Aguilar, A.O. (Oxford University Press, 2019)
      Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged <5 years in low- and middle-income countries. Although antibiotic treatment can be effective, emerging antimicrobial resistance, limited access, and cost affirm the role of vaccines as the most attractive countermeasure. Controlled human infection models (CHIMs) represent a valuable tool for assessing vaccine efficacy and potentially accelerating licensure. Currently, immunological analysis during CHIM studies is customized based on vaccine type, regimen, and administration route. Additionally, differences in type of immunoassays and procedures used limit comparisons across studies. In November 2017, an expert working group reviewed Shigella CHIM studies performed to date and developed consensus guidelines on prioritization of immunoassays, specimens, and collection time points. Immunoassays were ranked into 3 tiers, with antibodies to Shigella lipopolysaccharide (LPS) being the highest priority. To facilitate comparisons across clinical studies, a second workshop was conducted in December 2017, which focused on the pathway toward a recognized enzyme-linked immunosorbent assay (ELISA) to determine serum immunoglobulin G titers against Shigella LPS. The consensus of the meeting was to establish a consortium of international institutions with expertise in Shigella immunology that would work with the National Institute for Biological Standards and Control to establish a harmonized ELISA, produce a reference sera, and identify a reliable source of Shigella LPS for global utilization. Herein we describe efforts toward establishing common procedures to advance Shigella vaccine development, support licensure, and ultimately facilitate vaccine deployment and uptake. Copyright The Author(s) 2019.
    • Deletions in guaBA and htrA but not clpX or rfaL constitute a live-attenuated vaccine strain of Salmonella Newport to protect against serogroup C2-C3 Salmonella in mice

      Fuche, Fabien J.; Jones, Jennifer A.; Ramachandran, Girish; Higginson, Ellen E.; Simon, Raphael; Tennant, Sharon M. (Taylor and Francis Inc., 2019-07-12)
      Non-typhoidal Salmonella (NTS) are a leading cause of foodborne infections worldwide, and serogroups B, C1, C2-C3 and D are the most common serogroups associated with human disease. While live vaccine candidates that protect against S. Typhimurium (serogroup B) and S. Enteritidis (serogroup D) have been described by us and others, far less effort has been directed towards vaccines that target either serogroup C1 or C2-C3 Salmonella. Here we describe a Salmonella Newport-based live-attenuated vaccine (serogroup C2-C3). Deletion of the genes clpX or rfaL, previously used in live vaccines to attenuate S. Typhimurium and/or S. Enteritidis, failed to attenuate S. Newport. However, we found that deletion of either guaBA or htrA raised the 50% lethal dose of S. Newport in an intraperitoneal infection model in BALB/c mice. Our live-attenuated vaccine candidate CVD 1966 (S. Newport ΔguaBA ΔhtrA) elicited strong antibody responses against COPS, flagellin and outer membrane proteins when administered intraperitoneally or orally. Following lethal challenge with the parental virulent strain of S. Newport, we observed vaccine efficacies of 53% for immunization via the intraperitoneal route and 47% for immunization via the oral route. Following intraperiteonal immunization, the vaccine also significantly reduced the bacterial burden of challenge organisms in the liver and spleen. Interestingly, reducing the LPS chain length by deleting rfaL did not induce a stronger immune response towards surface antigens, and failed to elicit any protection against lethal homologous challenge. In conclusion, we have developed a live-attenuated Salmonella serogroup C2-C3 vaccine that we are further evaluating. © 2018 The Author(s).
    • Introduction of Typhoid Conjugate Vaccines in Africa and Asia

      Neuzil, K.M.; Pollard, A.J.; Marfin, A.A. (Oxford University Press, 2019)
      Typhoid fever continues to be a major public health concern, particularly in many low- and middle-income countries. The current threats of increasing antimicrobial resistance, urbanization, and climate change elevate the urgency for better prevention and control efforts for typhoid fever. In 2017, the results of ground-breaking research on typhoid conjugate vaccines (TCVs), the World Health Organization prequalification of a TCV, and global policy and financing decisions have set the stage for the introduction of TCVs into routine immunization programs in endemic countries. Country-level decision-making and program planning are critical for local uptake and sustainability. © 2019 The Author(s).
    • Maternal Antibodies Elicited by Immunization With an O- Polysaccharide Glycoconjugate Vaccine Protect Infant Mice Against Lethal Salmonella Typhimurium Infection

      Baliban, S.M.; Curtis, B.; Amin, M.N.; Levine, M.M.; Pasetti, M.F.; Simon, R. (Frontiers, 2019)
      Non-typhoidal Salmonella (NTS) are a leading cause of pediatric invasive bacterial infections in sub-Saharan Africa with high associated case fatality rates in children under 5 years old. We have developed glycoconjugate vaccines consisting of the lipid A-removed surface polysaccharide of NTS, core and O-polysaccharide (COPS), and the flagellar monomer protein (FliC) from the homologous serovar as the carrier. We previously established that COPS:FliC was immunogenic and protective in mice immunized as adults or infants; however, the brief period of murine infancy precluded the evaluation of protection against invasive NTS (iNTS) disease in early life. In the present study, we used a mouse model of maternal immunization to investigate transmission of S. Typhimurium COPS:FliC-induced maternal antibodies and protection against lethal iNTS challenge in infant mice. We found that vaccinated dams developed high levels of COPS- and FliC-specific IgG, which were transferred to their offspring. Sera from both vaccinated mothers and their litters mediated complement-dependent bactericidal activity in-vitro. Passively immunized 2-week old infant mice born to vaccinated mothers were fully protected from challenge with an S. Typhimurium blood isolate from sub-Saharan Africa. The pre-clinical findings reported herein demonstrate that anti-COPS:FliC antibodies induced by vaccination are sufficient for protection of murine infants against experimental S. Typhimurium infection. By underscoring the protective role of antibody, our results suggest that maintaining an adequate titer of protective anti-Salmonella antibodies during early life, either through pediatric or maternal COPS:FliC vaccination, may reduce iNTS disease in young children in sub-Saharan Africa.
    • The Time is Now to Control Typhoid

      Pollard, A.J.; Marfin, A.A.; Neuzil, K.M. (Oxford Academic, 2019)