Background. Vaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced significant serum functional activity in both US and Malian adults. However, antibody titers declined rapidly, and transmission-reducing activity required four vaccine doses. Functional immunogenicity and durability must be improved before advancing TBV further in clinical development. We hypothesized that the pre-fertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.Methods. Transmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody titers were measured by ELISA and transmission-reducing activity was assess by the Standard Membrane Feeding Assay. Results. Pfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In U.S. adults, two vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in five Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.Conclusion. The complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model. Trial Registration. ClinicalTrials.gov NCT02334462Funding. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Sara A. Healy, Charles F. Anderson, Bruce J. Swihart, Agnes Mwakingwe-Omari, Erin E. Gabriel, Hope Decederfelt, Charlotte V. Hobbs, Kelly M. Rausch, Daming Zhu, Olga Muratova, Raul Herrera, Puthupparampil V. Scaria, Nicholas J. MacDonald, Lynn E. Lambert, Irfan Zaidi, Camila H. Coelho, Jonathan P. Renn, Yimin Wu, David L. Narum, Patrick E. Duffy
BACKGROUND. Immunization with replication-competent recombinant vectors provides exposure to transgene-encoded antigens in the context of inflammation that may drive more potent and durable immunity compared to non-replicating vaccines. To understand the features of a replicating vaccine that drive such responses we tested a replication-competent adenovirus type 4 encoding influenza virus H5 hemagglutinin (Ad4-H5-Vtn) administered by an oral capsule or via a tonsillar swab or nasal spray. METHODS. Viral shedding from the nose, mouth, and rectum was measured by PCR and culture. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition assay (PVEI), microneutralization (MN), and hemagglutinin inhibition (HAI). RESULTS. Ad4-H5-Vtn DNA was shed from most upper respiratory tract (URT)-immunized volunteers for 2-4 weeks, but cultured from only 60% of participants with a median duration of one day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood and IgG and IgA in nasal, cervical and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAb) to H5 which remained stable at week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AE) were mild, and peak NAb titer was associated with overall AE frequency or duration. Serum neutralizing antibody titers could be boosted to very high levels 2-5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine. CONCLUSION. Replicating Ad4 delivered to the URT causes prolonged exposure to antigen, drives durable systemic and mucosal immunity, and is a promising platform for the induction of immunity against viral surface glycoprotein targets. TRIAL REGISTRATION. ClinicalTrials.gov NCT01443936, NCT01806909. FUNDING. Intramural and Extramural Research Programs of the NIAID, NIH; and the Centers of Influenza Virus Research and SurveillanceFunding. Intramural and Extramural Research Programs of the NIAID, NIH; and the Centers of Influenza Virus Research and Surveillance.
Kenta Matsuda, Stephen A. Migueles, Jinghe Huang, Lyuba Bolkhovitinov, Sarah Stuccio, Trevor Griesman, Alyssa A. Pullano, Byong H. Kang, Elise Ishida, Matthew Zimmerman, Neena Kashyap, Kelly M. Martins, Daniel Stadlbauer, Jessica Pederson, Andy Patamawenu, Nathaniel E. Wright, Tulley Shofner, Sean Evans, C. Jason Liang, Julián Candia, Angelique Biancotto, Giovanna Fantoni, April Poole, Jonathan Smith, Jeff Alexander, Marc Gurwith, Florian Krammer, Mark Connors
BACKGROUND. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused over one million deaths worldwide, thus there is an urgent need to develop preventive and therapeutic strategies. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) demonstrates non-specific protective innate immune-boosting effects. Here, we determined if history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a retrospective observational study of a diverse cohort of health care workers (HCWs). METHODS. We assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, including BCG vaccination status and pre-existing demographic and clinical characteristics, from an observational cohort of HCWs in a multi-site Los Angeles healthcare organization. We used multi-variate analysis to estimate if history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion. RESULTS. Of the 6,201 HCWs, 29.6% reported a history of BCG vaccination whereas 68.9% did not receive BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as incidence of self-reported clinical symptoms associated with COVID-19 were significantly decreased among HCWs with a history of BCG vaccination compared to those without BCG vaccination. After adjusting for age and sex, we found that history of BCG vaccination, but not meningococcal, pneumococcal or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion. CONCLUSIONS. History of BCG vaccination was associated with decreased seroprevalence of anti-SARS-CoV-2 IgG and reduced reported COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized prospective clinical trials of BCG vaccination are urgently needed to confirm if BCG vaccination can induced a protective effect against SARS-CoV2 infection. FUNDING. This work was supported by the National Institutes of Health, National Cancer Institute (U54 CA26059) and the Erika J. Glazer Family Foundation. Key words: SARS-CoV-2, COVID-19, Bacillus Calmette-Guérin, BCG, anti-SARS-CoV-2 IgG, healthcare workers, trained immunity.
Magali Noval Rivas, Joseph E. Ebinger, Min Wu, Nancy Sun, Jonathan Braun, Kimia Sobhani, Jennifer E. Van Eyk, Susan Cheng, Moshe Arditi
BACKGROUND Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODS We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients’ tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTS The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSION This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATION Phase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDING Center for Clinical Research, NCI, NIH.
Gal Cafri, Jared J. Gartner, Tal Zaks, Kristen Hopson, Noam Levin, Biman C. Paria, Maria R. Parkhurst, Rami Yossef, Frank J. Lowery, Mohammad S. Jafferji, Todd D. Prickett, Stephanie L. Goff, Christine T. McGowan, Samantha Seitter, Mackenzie L. Shindorf, Anup Parikh, Praveen D. Chatani, Paul F. Robbins, Steven A. Rosenberg
After over three decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine, but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates for the first time that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.
Hongzhao Li, Robert W. Omange, Binhua Liang, Nikki Toledo, Yan Hai, Lewis R. Liu, Dane Schalk, Jose Crecente-Campo, Tamara G. Dacoba, Andrew B. Lambe, So-Yon Lim, Lin Li, Mohammad Abul Kashem, Yanmin Wan, Jorge F. Correia-Pinto, Michael S. Seaman, Xiao-Qing Liu, Robert F. Balshaw, Qingsheng Li, Nancy Schultz-Darken, Maria Jose Alonso, Francis A. Plummer, James B. Whitney, Ma Luo
BACKGROUND. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes towards protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. 18 volunteers were vaccinated with BCG at 6pm and compared with 36 age- and sex-matched volunteers vaccinated between 8-9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as two weeks and three months after BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8am-12pm with BCG. RESULTS. Compared to evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning compared to evening isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared to evening vaccination. Future studies should take vaccine administration time into account when studying specific and non-specific effects of vaccines: early morning should be the preferred moment of BCG administration. FUNDING Spinoza grant of the Netherlands Organization for Scientific Research, ERC Advanced Grant (TRAIN-OLD nr. 833247), Danish National Research Foundation (DNRF108).
L. Charlotte J. de Bree, Vera P. Mourits, Valerie A.C.M. Koeken, Simone J.C.F.M. Moorlag, Robine Janssen, Lukas Folkman, Daniele Barreca, Thomas Krausgruber, Victoria Fife-Gernedl, Boris Novakovic, Rob J.W. Arts, Helga Dijkstra, Heidi Lemmers, Christoph Bock, Leo A.B. Joosten, Reinout van Crevel, Christine S. Benn, Mihai G. Netea
Background. Induction of innate immune memory, also termed trained immunity, by the anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known: while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases. Methods. We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis and Staphylococcus aureus induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity. Results. While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in three smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination. Conclusion. The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications. Funding. This study was funded by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant (TRAIN-OLD nr. 833247).
Valerie A. C. M. Koeken, L. Charlotte J. de Bree, Vera P. Mourits, Simone J.C.F.M. Moorlag, Jona Walk, Branko Cirovic, Rob J.W. Arts, Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Leo A.B. Joosten, Christine Stabell Benn, Reinout van Crevel, Mihai Netea
Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression.
Wenqiang Cao, Fengqin Fang, Timothy Gould, Xuanying Li, Chulwoo Kim, Claire Gustafson, Simon Lambert, Cornelia M. Weyand, Jörg J. Goronzy
Backgroun NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells; these functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined. Methods The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analysed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen, and in response to in vitro Ebola glycoprotein stimulation of PBMC isolated before and after vaccination. Results We show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whilst IFN-γ secretion was restricted by high concentrations of IL-10. Conclusion This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola GP. Trial registration ClinicalTrials.gov Identifier: NCT02313077 Funding U.K. Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (Grant 115861) and Crucell Holland (now Janssen Vaccines & Prevention B.V.), European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA).
Helen R. Wagstaffe, Elizabeth A. Clutterbuck, Viki Bockstal, Jeroen N. Stoop, Kerstin Luhn, Macaya J. Douoguih, Georgi Shukarev, Matthew D. Snape, Andrew J. Pollard, Eleanor M. Riley, Martin Goodier
Background: Interventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naïve individuals. Method: Healthy, malaria-naïve adults were enrolled in two studies to assess the safety and infectivity and transmissibility of a new P. vivax isolate. Participants (Study 1; n=2, Study 2; n=24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes. Results: Parasitaemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Participants were infectious to Anopheles mosquitoes at peak gametocytemia 69% (11/16). Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture. Conclusion: We have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle. Trial registration: ACTRN12614000930684 and ACTRN12616000174482. Funding: (Australian) NHMRC Program Grant: 1132975 (Study 1). Bill & Melinda Gates Foundation (OPP1111147) (Study 2).
Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Gregory J. Robinson, Melanie Rampton, Suzanne Elliott, Anand Odedra, David S. Khoury, Emma Ballard, Todd B. Shelper, Leonardo Lucantoni, Vicky M. Avery, Stephan Chalon, Jörg J. Möhrle, James S. McCarthy
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