Papers of the Month – 2015

December, 2015

Veterinary Microbiology 182 (2016) 178–186.

Jiwoon Jeong, Changhoon Park, Kyuhyung Choi, Chanhee Chae

The efficacy of the new single-dose bivalent vaccine of porcine circovirus type 2 (PCV2) and Mycoplasma hyopneumoniae was evaluated under field conditions for registration as recommended by the Republic of Korea’s Animal, Plant & Fisheries Quarantine & Inspection Agency. Three farms were selected based on their history of co-infection with PCV2 and M. hyopneumoniae. On each farm, a total of 80 3-week-old pigs were randomly allocated to one of two treatment groups: (i) vaccinated (n = 40) and (ii) unvaccinated (n = 40) animals at 3 weeks of age. Protection by the bivalent vaccine helped increase the market weight by 6.2 kg/pig (106.2 kg in vaccinated group vs. 100 kg in unvaccinated group; P < 0.05) and decreased mortality rate by 13.4% (0.8% in unvaccinated group vs.14.2% in unvaccinated group; P < 0.05). Vaccinated animals induced PCV2-specific neutralizing antibodies (NA) and interferon-g secreting cells (IFN-g-SC), and M. hyopneumoniae-specific IFN-g-SC. Vaccinated animals displayed a reduced PCV2 load in the blood and M. hyopneumoniae load in nasal swabs compared to unvaccinated animals. Vaccination of pigs against PCV2 and M. hyopneumoniae effectively reduced the lung and lymphoid lesion scores compared to unvaccinated animals in all 3 farms. The new bivalent vaccine is very efficacious in controlling PCV2 and M. hyopneumoniae infection based on clinical, immunological, virological, and pathological evaluations under field conditions.


November, 2015

2015. Journal of Infectious Diseases. In press.

Steven Black, Uwe Nicolay, Giuseppe Del Giudice and Rino Rappuoli

Influenza vaccination strategies have targeted elderly individuals because they are at high risk of disease complications and mortality. Statins are a class of drugs used to treat hypercholesterolemia and are frequently used in the elderly population to reduce the risk of cardiovascular disease. However, statins are also known to have immunomodulatory effects that could impact influenza vaccine response. In a post hoc analysis, we performed a cross-sectional observational study nested within a comparative immunogenicity clinical trial of adjuvanted versus unadjuvanted influenza vaccine in elderly persons to evaluate the influence of statin therapy on the immune response to vaccination. Overall, data on >5000 trial participants were available for analysis. Comparison of hemagglutination-inhibiting geometric mean titers to influenza A(H1N1), A(H3N2), and B strains revealed that titers were 38% (95% confidence interval [CI], 27%–50%), 67% (95% CI, 54%–80%), and 38% (95% CI, 28%–29%) lower, respectively, in subjects receiving chronic statin therapy, compared with those not receiving chronic statin therapy. This apparent immunosuppressive effect of statins on the vaccine immune response was most dramatic in individuals receiving synthetic statins. These effects were seen in both the adjuvanted and unadjuvanted vaccine groups in the clinical trial. These results, if confirmed, could have implications both for future clinical trials design, as well as for vaccine use recommendations for elderly individuals.

October, 2015

Science Translational Medicine. 2015 Oct 21;7(310):310ra167. doi: 10.1126/scitranslmed.aac5477.

Mou Z, Li J, Boussoffara T, Rishi H, Hamana H, Ezzati P, Hu C, Yi W, Liu D, Khadem F, Okwor I, Jia P, Shitaoka K, Wang S, Ndao M, Petersen C, Chen J, Rafati S, Louzir H, Muraguchi A, Wilkins JA, Uzonna JE.

There is currently no clinically effective vaccine against leishmaniasis because of poor understanding of the antigens that elicit dominant T cell immunity. Using proteomics and cellular immunology, we identified a dominant naturally processed peptide (PEPCK335-351) derived from Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK). PEPCK was conserved in all pathogenic Leishmania, expressed in glycosomes of promastigotes and amastigotes, and elicited strong CD4(+) T cell responses in infected mice and humans. I-A(b)-PEPCK335-351 tetramer identified protective Leishmania-specific CD4(+) T cells at a clonal level, which comprised ~20% of all Leishmania-reactive CD4(+) T cells at the peak of infection. PEPCK335-351-specific CD4(+) T cells were oligoclonal in their T cell receptor usage, produced polyfunctional cytokines (interleukin-2, interferon-γ, and tumor necrosis factor), and underwent expansion, effector activities, contraction, and stable maintenance after lesion resolution. Vaccination with PEPCK peptide, DNA expressing full-length PEPCK, or rPEPCK induced strong durable cross-species protection in both resistant and susceptible mice. The effectiveness and durability of protection in vaccinated mice support the development of a broadly cross-species protective vaccine against different forms of leishmaniasis by targeting PEPCK.


September, 2015

Nature Medicine 21, 1065–1070 (2015) doi:10.1038/nm.3927

Yassine HM, Boyington JC, McTamney PM, Wei CJ, Kanekiyo M, Kong WP, Gallagher JR, Wang L, Zhang Y, Joyce MG, Lingwood D, Moin SM, Andersen H, Okuno Y, Rao SS, Harris AK, Kwong PD, Mascola JR, Nabel GJ, Graham BS.

The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes1, 2, 3, 4, 5, 6. Here we report the structure-based development of an H1 HA stem–only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1–Gen6) yielded successive H1 HA stabilized-stem (HA–SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA–SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA–SS on ferritin nanoparticles (H1–SS–np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1–SS–np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1–SS–np–immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem–specific antibodies can protect against diverse group 1 influenza strains.

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen.

Science. 2015 Sep 18;349(6254):1301-6. doi: 10.1126/science.aac7263. Epub 2015 Aug 24.

Impagliazzo A, Milder F, Kuipers H, Wagner MV, Zhu X, Hoffman RM, van Meersbergen R, Huizingh J, Wanningen P, Verspuij J, de Man M, Ding Z, Apetri A, Kükrer B, Sneekes-Vriese E, Tomkiewicz D, Laursen NS, Lee PS, Zakrzewska A, Dekking L, Tolboom J, Tettero L, van Meerten S, Yu W, Koudstaal W, Goudsmit J, Ward AB, Meijberg W, Wilson IA, Radošević K.

The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens (“mini-HAs”) based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.

August, 2015

Shu Chen, Zi Zhou, Fei-Xue Wei, Shou Jie Huang, Zhong Tan, Ya Fang, Feng-Cai Zhu, Ting Wu, Jun Zhang, Ning-Shao Xia

Background: The first commercialized hepatitis E vaccine, HEV 239, has been shown to be safe and highly immunogenic, the protection as well as the vaccine-induced anti-HEV maintained for at least 4.5 years. However, the longer term persistence of the vaccine-induced anti-HEV responses is unknown.

Methods: Two statistical models, the power-law model and the modified power-law model, were applied to predict the long-term antibody response of the HEV 239 vaccine. The models were fit using the anti-HEV IgG data from a modeling subpopulation of 1278 baseline seronegative vaccinees who seroconverted within one month after finishing the whole vaccination course in the phase 3 trial of HEV 239. In addition, antibody data from a validation subpopulation were used to validate the robustness of the derived models.

Results: In the vaccinees without pre-vaccination immunity, the power-law model and the modified power-law model estimated that the median duration of the detectable antibody (≥0.077WU/ml) was 8 years and 13 years, respectively. The power-law model and the modified power-law model estimated that 50% of these vaccinees will maintain detectable levels of anti-HEV IgG for 8 years and >30 years, respectively.

Conclusions: The recombinant hepatitis E vaccine HEV 239 is predicted to provide from 8 years to nearly life-long persistence of anti-HEV IgG above detectable levels. Model predictions are based on conservative mathematical assumptions. (NCT01014845).

July, 2015

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June, 2015

J Infect Dis. 2015 Jul 15;212 Suppl 1:S12-6. doi: 10.1093/infdis/jiu568.

Stanley A. Plotkin.

Vaccines already developed have been enormously successful. However, the development of future vaccines requires solution of a number of immunologic problems, including pathogen variability, short effector memory, evoking functional responses, and identification of antigens that generate protective responses. In addition, different populations may respond differently to the same vaccine because of genetic, age, or environmental factors

May, 2015

Monica A. McArthur, Stephanie Fresnay, Laurence S. Magder, Thomas C. Darton, Claire Jones, Claire S. Waddington, Christoph J. Blohmke, Gordon Dougan, Brian Angus, Myron M. Levine, Andrew J. Pollard, Marcelo B. Sztein

Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.

April, 2015

Bonten MJ, Huijts SM, Bolkenbaas M, Webber C, Patterson S, Gault S, van Werkhoven CH, van Deursen AM, Sanders EA, Verheij TJ, Patton M, McDonough A, Moradoghli-Haftvani A, Smith H, Mellelieu T, Pride MW, Crowther G, Schmoele-Thoma B, Scott DA, Jansen KU, Lobatto R, Oosterman B, Visser N, Caspers E, Smorenburg A, Emini EA, Gruber WC, Grobbee DE.

Background: Pneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown.

Methods: In a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease.

Results: In the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community-acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group.

Conclusion: Among older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA number NCT00744263.).

March, 2015

Lancet Respir Med 2015 Mar;3(3):190-200

Birahim Pierre Ndiaye, MD, Friedrich Thienemann, MD, Martin Ota, FWACP, Bernard S Landry, MPHf, Makhtar Camara, PhD, Siry Dièye, MD, Tandakha Ndiaye Dieye, PhD, Hanif Esmail, MRCP, j, Rene Goliath, BSc, Kris Huygen, PhD, Vanessa January, Ibrahima Ndiaye, MD, Tolu Oni, MD, c, Michael Raine, BSc, Marta Romano, PhD, Iman Satti, PhD, Sharon Sutton, BS, Aminata Thiam, MD, Katalin A Wilkinson, PhD, Prof Souleymane Mboup, PhD, Prof Robert J Wilkinson, FRCP, †, Prof Helen McShane, FRCP, , †, , for the MVA85A 030 trial investigators‡

Background: HIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.

Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18-50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6-12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with, number NCT01151189.

Findings: Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI -41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI -111·5 to 80·3).

Interpretation:MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.

Findings: European & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.

February, 2015

Kimberly A. Kraynyak, Angela Bodles-Brakhop and Mark Bagarazzi

Cancer is a worldwide leading cause of death, and current conventional therapies are limited. The search for alternative preventive or therapeutic solutions is critical if we are going to improve outcomes for patients. The potential for DNA vaccines in the treatment and prevention of cancer has gained great momentum since initial findings almost 2 decades ago that revealed that genetically engineered DNA can elicit an immune response. The combination of adjuvants and an effective delivery method such as electroporation is overcoming past setbacks for naked plasmid DNA (pDNA) as a potential preventive or therapeutic approach to cancer in large animals and humans. In this chapter, we aim to focus on the novel advances in recent years for DNA cancer vaccines, current preclinical data, and the impor- tance of adjuvants and electroporation with emphasis on prostate, melanoma, and cervical cancer.

January, 2015

Journal of Immunology.2015 Feb 2. pii: 1402228. [Epub ahead of print].

A. Silva, A. Mount, K. Krstevska, D. Pejoski, M.P. Hardy, C. Owczarek, P. Scotney, E. Maraskovsky, A. Baz Morelli.

The development of therapeutic vaccines for treatment of established cancer has proven challenging. Cancer vaccines not only need to induce a robust tumor Ag-specific immune response but also need to overcome the tolerogenic and immunosuppressive microenvironments that exist within many solid cancers. ISCOMATRIX adjuvant (ISCOMATRIX) is able to induce both tumor Ag-specific cellular and Ab responses to protect mice against tumor challenge, but this is insufficient to result in regression of established solid tumors. In the current study, we have used B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer mouse tumor models to test therapeutic efficacy of ISCOMATRIX vaccines combined with other immune modulators. The coadministration of an ISCOMATRIX vaccine with the TLR3 agonist, polyinosinic-polycytidylic acid, and TLR9 agonist, CpG, reduced tumor growth in all tumor models and the presence of ISCOMATRIX in the formulation was critical for the therapeutic efficacy of the vaccine. This vaccine combination induced a robust and multifunctional CD8+ T cell response. Therapeutic protection required IFN-γ and CD8+ T cells, whereas NK and CD4+ T cells were found to be redundant. ISCOMATRIX vaccines combined with TLR3 and TLR9 agonists represent a promising cancer immunotherapy strategy.

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