Vaccine Immunology Research Articles

The Immunologic Complexity of Growing Up with Malaria—Is Scientific Understanding Coming of Age?

In the current issue of Clinical and Vaccine Immunology, Mandala et al. report changes in lymphocyte populations in children with uncomplicated malaria, severe malarial anemia, and cerebral malaria compared to controls (W. L. Mandala et al., Clin Vaccine Immunol 23:95-103, 2016, http://dx.doi.org/10.1128/CVI.00564-15). This commentary discusses the importance of understanding both helpful and detrimental aspects of the antimalarial immune response that are critical to malaria vaccine development and considers how these responses may relate to antimalarial vaccine safety and efficacy.

Immunological surrogate endpoints to evaluate vaccine efficacy

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

Acknowledgment ofAd HocReviewers

The Editors of Clinical and Vaccine Immunology (CVI) are deeply grateful to the ad hoc reviewers who contributed their time and expertise reviewing manuscripts during the period from October 2012 through September 2013. We greatly appreciate your efforts and invaluable support to maintain the

What to do about pertussis vaccines? Linking what we know about pertussis vaccine effectiveness, immunology and disease transmission to create a better vaccine.

Pertussis (whooping cough) is a respiratory disease caused by the bacterium Bordetella pertussis. Despite the implementation of immunization programs and high vaccine coverage in most jurisdictions, pertussis is still one of the most common vaccine-preventable diseases, suggesting that the current vaccines and immunization schedules have not been sufficiently effective. Several factors are thought to contribute to this. The acellular pertussis vaccine that has been used in many jurisdictions since the 1990s is less effective than the previously used whole-cell vaccine, with immunity waning over time. Both whole-cell and acellular pertussis vaccines are effective at reducing disease severity but not transmission, resulting in outbreaks in vaccinated cohorts. In this review, we discuss various limitations of the current approaches to protection from pertussis and outline various options for reducing the burden of pertussis on a population level.

Immune response in infants after universal high-dose hepatitis B vaccination: A community-based study in Beijing, China

BackgroundVaccination of infants beginning at birth is recommended to prevent Hepatitis B virus (HBV) infection in China. Compared to 5μg/dose vaccine administered in other regions in China, a three-dose HB recombinant yeast vaccine at 10μg/dose has been administered for infants within 24h after birth, 1 month and 6 months of age in Beijing since 2006. In a community-based retrospective cohort study, factors influencing immunologic vaccine response were evaluated. MethodsA total of 3670 infants who completed a 3-dose 10μg recombinant HB vaccine regimen and born to hepatitis B antigen negative mothers were included. The effect on anti-HBs titers of maternal nutrient status, infants’ birth condition, growth factors, timeliness of vaccination, dosing interval and the interval until post-vaccination serologic testing (PVST) were evaluated. ResultsA total of 3666 infants with no markers of HBV infection were included in analysis. The mean anti-HB titers were 1767.17mIU/ml. Only 16.9% of the infants completed their PVST within 30–59 days after the final dose of vaccination. Multivariate linear regression analysis showed that delay in PVST (β=−0.097, p<0.0001) and maternal folic acid supplementation (β=0.067, p=0.002) were associated with log-transformed anti-HB titers. Also a trend toward significant association was observed between the calcium supplementation of infants and log-transformed anti-HBs titers (β=0.062, p=0.057). Longer interval between dose 2 and dose 3 was not observed to increase the anti-HB titers after cofactors adjustment. ConclusionsOur findings illustrate the importance of timing of PVST to avoid unnecessary revaccination. Multi-center large cohort studies should verify the effect and magnitude of folate and calcium supplementation on HB vaccine response.

Ovarian cancer: early detection, angiogenesis, lymphangiogenesis and current prospects for therapy

Abstract I Chair and Department of Gynecological Oncology and Gynecology is a specialist research center providing help in diagnostics and treatment of gynecological malignancies. The research work is focused on the processes of angiogenesis and lymphangiogenesis. Development of blood and lymphatic vessels is subject to research in a wide range of malignancies, including ovarian cancer, endometrial cancer and uterine sarcomas. Angiogenesis in malignancies of the female genital tract is investigated by using some modern 3D sonography that uses high-definition blood flow imaging. Ovarian Tumors and Early Ovarian Cancer Detection unit was established in 2002 and since that time more than 3500 patients with difficult to diagnose tumors have been consulted and treated in the Department. Ovarian cancer immunology studies are the second leading research fiekld in the 1st Chair Department of Gynecological Oncology and Gynecology. The Department is well equipped with diagnostic devices as well as a scientific laboratory. This allows for studies in the fields of imaging of masses, their immunology, biochemistry and molecular biology. Understanding immunological response in patients with ovarian cancer is the key to develop new, effective therapies, including immunological vaccines. In this area we are cooperating with prominent international research centers: Department of Surgery, University of Michigan and Department of Microbiology and Immunology, University of Arkansas. Results of our research are published in both Polish and international journals specializing in fields of gynecology, oncology, immunology and basic science.

Size Dependent Variations of Phospholipid Based Vesicular Drug Carriers in Systemic Drug Activity

Lipid based vesicular drug delivery system, one of the emerging technologies designed for addressing the delivery challenges of conventional drug delivery methods, has widespread applications in chemotherapeutics, immunotherapeutics, recombinant DNA technology, membrane biology and also as a diagnostic tool in different biological field. The enclosed phospholipid bilayer spherical structure, typically known as liposome, is a versatile vesicular delivery system to carry hydrophilic/hydrophobic drug generally efficiently to the site of action leading to reduced non-specific toxicity and improved bioavailability of the therapeutic moiety. Efficacy of drug encapsulated in liposome depends mainly on the circulation amount of liposome and its residence time, in vivo drug release, drug accumulation in the target site and uptake of the formulation in the reticuloendothelial system. Liposomal formulation factors that dictate those actions are liposomal size (hydrodynamic diameter), surface charge, lipid composition and steric stabilization. Variation in liposomal size shows around 100 fold alterations in pharmacokinetic parameters and systemic activity while the other factors such as surface charge, lipid composition and steric stabilization bring only about 10 fold changes in those properties. The findings indicate the critical role of vesicular size in liposomal efficacy. In the present review the effect of size-variation of liposome on systemic activity of drug as well as its pharmacokinetic profile will be discussed to understand the rational designing of liposomal preparation to maximize therapeutic activity of a drug at desired magnitude and to provide a wide range of product applications such as immunological vaccines, chemotherapy, antimicrobial therapy etc.

Calibration weighted estimation of semiparametric transformation models for two-phase sampling.

Two-phase designs are commonly used to subsample subjects from a cohort in order to study covariates that are too expensive to ascertain for everyone in the cohort. This is particularly true for the study of immune response biomarkers in vaccine immunology, where new, elaborate assays are constantly being developed to improve our understanding of the human immune responses to vaccines and how the immune response may protect humans from virus infection. It has long being recognized that if there exist variables that are correlated with expensive variables and can be measured for every subject in the cohort, they can be leveraged to improve the estimation efficiency for the effects of the expensive variables. In this research article, we developed an improved inverse probability weighted estimation approach for semiparametric transformation models with a two-phase study design. Semiparametric transformation models are a class of models that include the Cox PH and proportional odds models. They provide an attractive way to model the effects of immune response biomarkers as human immune responses generally wane over time. Our approach is based on weights calibration, which has its origin in survey statistics and was used by Breslow et al. to improve inverse probability weighted estimation of the Cox regression model. We develop asymptotic theory for our estimator and examine its performance through simulation studies. We illustrate the proposed method with application to two HIV-1 vaccine efficacy trials.

A Review of Intra- and Extracellular Antigen Delivery Systems for Virus Vaccines of Finfish.

Vaccine efficacy in aquaculture has for a long time depended on evaluating relative percent survival and antibody responses after vaccination. However, current advances in vaccine immunology show that the route in which antigens are delivered into cells is deterministic of the type of adaptive immune response evoked by vaccination. Antigens delivered by the intracellular route induce MHC-I restricted CD8+ responses while antigens presented through the extracellular route activate MHC-II restricted CD4+ responses implying that the route of antigen delivery is a conduit to induction of B- or T-cell immune responses. In finfish, different antigen delivery systems have been explored that include live, DNA, inactivated whole virus, fusion protein, virus-like particles, and subunit vaccines although mechanisms linking these delivery systems to protective immunity have not been studied in detail. Hence, in this review we provide a synopsis of different strategies used to administer viral antigens via the intra- or extracellular compartments. Further, we highlight the differences in immune responses induced by antigens processed by the endogenous route compared to exogenously processed antigens. Overall, we anticipate that the synopsis put together in this review will shed insights into limitations and successes of the current vaccination strategies used in finfish vaccinology.

A new model for catalyzing translational science: the early stage investigator mentored research scholar program in HIV vaccines.

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large-scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.

Correction for Chakrabarti et al., Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Bimal K. Chakrabarti, Yu Feng, Shailendra Kumar Sharma, Krisha McKee, Gunilla B. Karlsson Hedestam, Celia C. LaBranche, David C. Montefiori, John R. Mascola, Richard T. Wyatt IAVI Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, USA; The Vaccine Research Center, NIH, Bethesda, Maryland, USA; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA; The Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells

The Center for HIV/AIDS Vaccine Immunology (CHAVI) consortium was established to determine the host and virus factors associated with HIV transmission, infection and containment of virus replication, with the goal of advancing the development of an HIV protective vaccine. Studies to meet this goal required the use of cryopreserved Peripheral Blood Mononuclear Cell (PBMC) specimens, and therefore it was imperative that a quality assurance (QA) oversight program be developed to monitor PBMC samples obtained from study participants at multiple international sites. Nine site-affiliated laboratories in Africa and the USA collected and processed PBMCs, and cryopreserved PBMC were shipped to CHAVI repositories in Africa and the USA for long-term storage. A three-stage program was designed, based on Good Clinical Laboratory Practices (GCLP), to monitor PBMC integrity at each step of this process. The first stage evaluated the integrity of fresh PBMCs for initial viability, overall yield, and processing time at the site-affiliated laboratories (Stage 1); for the second stage, the repositories determined post-thaw viability and cell recovery of cryopreserved PBMC, received from the site-affiliated laboratories (Stage 2); the third stage assessed the long-term specimen storage at each repository (Stage 3). Overall, the CHAVI PBMC QA oversight program results highlight the relative importance of each of these stages to the ultimate goal of preserving specimen integrity from peripheral blood collection to long-term repository storage.

Serological diagnostic assays for HIV-associated tuberculosis in sub-Saharan Africa?

In this issue of Clinical and Vaccine Immunology, Siev and colleagues present an evaluation of antibody responses to four immunodominant proteins of Mycobacterium tuberculosis in patients with HIV-associated pulmonary tuberculosis (TB) in South Africa (M. Siev, D. Wilson, S. Kainth, V. O. Kasprowicz, C. M. Feintuch, E. Jenny-Avital, and J. J. Achkar, 21:791-798, 2014, doi:http://dx.doi.org/10.1128/CVI.00805-13). This commentary discusses the enormous need for simple point-of-care assays for tuberculosis (TB) diagnosis in patients with and without HIV coinfection in high-burden settings and considers the potential role of serological assays and the huge challenges inherent in developing and validating such assays.

Modified Vaccinia Virus Ankara as Vaccine Vectors in Human and Veterinary Medicine

ABSTRACT: Disease prevention through vaccination is one of the most important achievements of medicine. Today, we have a substantial number of vaccines against a variety of pathogens. In this context, poxviruses and vaccinology are closely related, as the birth of modern vaccinology was marked by the use of poxviruses as immunogens and so was the eradication of smallpox, one of the world's most feared diseases ever. Nowadays, poxviruses continue to notoriously contribute to vaccinology since their use as vaccine vectors has become popular and widespread. One of the most promising vectors is the modified vaccinia ankara. In this review we provide an overview of the contribution of poxvirus to vaccine immunology, particularly focusing on modified vaccinia ankara-based vaccines developed to date.

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells

Comparing the roles of antibodies to nontyphoidal Salmonella enterica in high- and low-income countries and implications for vaccine development.

The article by Trebicka et al. (1) in the current issue of Clinical and Vaccine Immunology on antibodies to Salmonella among adults and children in the US, is paradoxically important for our understanding of immunity to nontyphoidal Salmonella (NTS) globally, and the development of a much-needed vaccine for Africa.…

Deciphering the impacts of vaccination and immunity on pertussis epidemiology in Thailand

Pertussis is a highly infectious respiratory disease that is currently responsible for nearly 300,000 annual deaths worldwide, primarily in infants in developing countries. Despite sustained high vaccine uptake, a resurgence in pertussis incidence has been reported in a number of countries. This resurgence has led to critical questions regarding the transmission impacts of vaccination and pertussis immunology. We analyzed pertussis incidence in Thailand--both age-stratified and longitudinal aggregate reports--over the past 30 y. To dissect the contributions of waning pertussis immunity and repeat infections to pertussis epidemiology in Thailand following a pronounced increase in vaccine uptake, we used likelihood-based statistical inference methods to evaluate the support for multiple competing transmission models. We found that, in contrast to other settings, there is no evidence for pertussis resurgence in Thailand, with each model examined pointing to a substantial rise in herd immunity over the past 30 y. Using a variety of empirical metrics, we verified our findings by documenting signatures of changing herd immunity over the study period. Importantly, this work leads to the conclusion that repeat infections have played little role in shaping pertussis epidemiology in Thailand. Our results are surprisingly emphatic in support of measurable impact of herd immunity given the uncertainty associated with pertussis epidemiology.

Serum Antibodies to Blood Group A Predict Survival on PROSTVAC-VF

There is evidence that therapeutic cancer vaccines can lengthen survival for some patients with cancer, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy. This retrospective study included 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan-Meier survival estimates. Because of the potential for overfitting, a permutation test was used to estimate the false discovery rate. Prevaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri immunoglobulin M (IgM) relative to subjects with little or no preexisting IgM for BG-Atri. This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate-specific antigen (PSA). Moreover, anti-BG-Atri IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival. In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the use of glycan microarray technology for improving our understanding of vaccine immunology. Clin Cancer Res; 19(5); 1290-9. ©2012 AACR.

Ancillary study management systems: a review of needs.

BackgroundThe valuable clinical data, specimens, and assay results collected during a primary clinical trial or observational study can enable researchers to answer additional, pressing questions with relatively small investments in new measurements. However, management of such follow-on, “ancillary” studies is complex. It requires coordinating across institutions, sites, repositories, and approval boards, as well as distributing, integrating, and analyzing diverse data types. General-purpose software systems that simplify the management of ancillary studies have not yet been explored in the research literature.MethodsWe have identified requirements for ancillary study management primarily as part of our ongoing work with a number of large research consortia. These organizations include the Center for HIV/AIDS Vaccine Immunology (CHAVI), the Immune Tolerance Network (ITN), the HIV Vaccine Trials Network (HVTN), the U.S. Military HIV Research Program (MHRP), and the Network for Pancreatic Organ Donors with Diabetes (nPOD). We also consulted with researchers at a range of other disease research organizations regarding their workflows and data management strategies. Lastly, to enhance breadth, we reviewed process documents for ancillary study management from other organizations.ResultsBy exploring characteristics of ancillary studies, we identify differentiating requirements and scenarios for ancillary study management systems (ASMSs). Distinguishing characteristics of ancillary studies may include the collection of additional measurements (particularly new analyses of existing specimens); the initiation of studies by investigators unaffiliated with the original study; cross-protocol data pooling and analysis; pre-existing participant consent; and pre-existing data context and provenance. For an ASMS to address these characteristics, it would need to address both operational requirements (e.g., allocating existing specimens) and data management requirements (e.g., securely distributing and integrating primary and ancillary data).ConclusionsThe scenarios and requirements we describe can help guide the development of systems that make conducting ancillary studies easier, less expensive, and less error-prone. Given the relatively consistent characteristics and challenges of ancillary study management, general-purpose ASMSs are likely to be useful to a wide range of organizations. Using the requirements identified in this paper, we are currently developing an open-source, general-purpose ASMS based on LabKey Server (http://www.labkey.org) in collaboration with CHAVI, the ITN and nPOD.

Insights from Natural Infection-Derived Immunity to Cholera Instruct Vaccine Efforts

Insights from Natural Infection-Derived Immunity to Cholera Instruct Vaccine Efforts