Atomic-level structural information and advances in synthetic biology and nanotechnology have created new opportunities for generating vaccines in a way that has not been possible using traditional methods. These novel approaches to recombinant vaccine design are opening doors to the development of vaccines against challenging targets. In this chapter, we discuss the exceptional humoral immunogenicity of virus-like particles (VLPs) and related nanoparticles and their application to vaccine development. The emergence of this new category of vaccine platforms is based on recent insights from multiple fields of study, including immunology, virology, nanotechnology, structural biology, synthetic biology, and bioengineering. The multidisciplinary work on VLP and nanoparticle immunogens is already yielding dividends for public health, but is also likely to result in safer, more potent and broadly protective vaccines against a wide variety of human and animal pathogens, as well as target host proteins of interest.
Whole-genome sequencing of bacteria and advances in bioinformatics have revolutionized the vaccinology field, leading to the identification of potential vaccine candidates without the need for cultivating the pathogen. This approach, termed "reverse vaccinology", reduces the time and cost required for the identification of candidate vaccines and provides new solutions for those diseases for which conventional approaches have failed. The first example of the potential of reverse vaccinology has been the identification of novel antigens of meningococcus B as potential candidates for a novel and effective vaccine. The same approach has been successfully applied to other important human pathogens, demonstrating the feasibility to develop vaccines against any infectious disease. This review focuses on some recent advances in the identification of vaccine candidates by mining the genomic sequences of pathogenic bacteria.
Genetic diversity has underpinned the survival and expansion of human populations against a long history of varied microbial challenges, but may limit the universal immunogenicity of current vaccines against particular pathogens. Reduced or non-responsiveness is a barrier to total pathogen eradication for established vaccines, and remains the key impediment to licensure for a number of investigational vaccines. Genetic association studies have identified some determinants of vaccine immunogenicity, many of which act at single molecular interactions within complex pathways and networks. To date these immune modifying polymorphisms explain only a fraction of the known variation in vaccine responses and the most striking aspect of individualized immunity, immunodominance, remains a central issue in new vaccine design. Vaccine personalization is likely to require not only a systems biology approach to understand broad vaccine response phenotypes, but also an understanding that the specificity of antigen recognition unique to every vaccinee and restricted by their human leukocyte antigen (HLA) genotype, determines the unique CD4 and CD8 T cell and natural killer (NK) cell repertoires available for vaccine induction. This chapter discusses the role of HLA and non-HLA loci, and pathogen-specific adaptations relevant to vaccines and explores ways these could be exploited in vaccine design and personalization.
As new vaccines are introduced and existing vaccines are targeted for new populations, it is important to understand the unique aspects of "special populations." The goal of this chapter is to identify these special populations, discuss their burden of vaccine preventable disease and evaluate their impact on vaccine policy. This chapter will also present the specific challenges and concerns with respect to vaccine immunogenicity, efficacy, and safety within these populations. It will also propose new areas of investigation into the optimization of these immunization parameters. The special populations to be considered include infants, pregnant women, and immunocompromised individuals and older adults. Each of these groups will be discussed separately in the context of representative vaccines.
This chapter considers the statistical evaluation of vaccine efficacy based on randomized, controlled, preventive vaccine efficacy trials. After defining concepts and target parameters for measuring vaccine efficacy, the remainder of the chapter focuses on studying unconditional vaccine efficacy to reduce susceptibility to pathogen infection or disease, measured cumulatively over time. A unified approach to studying how this type of vaccine efficacy depends on the following four factors is presented: baseline participant characteristics, biomarkers measuring immune responses to vaccination, genotypic and phenotypic characteristics of exposing pathogens, and time since vaccination. Statistical issues and design and analysis techniques for learning about such correlates of vaccine efficacy are discussed, including on the use of high-dimensional assays such as whole genome transcriptomic and mass cytometry assays.
Effective vaccines for numerous pathogens—including malaria, tuberculosis (TB), and human immunodeficiency virus (HIV)—remain elusive despite decades of research. Scores of HIV vaccine strategies have been proposed, with more than 550 phase I trials registered at clinicaltrials.gov (April 24, 2016). However, just six phase IIb/III vaccine efficacy trials have been conducted, testing only four concepts. The main challenge for pathogens like HIV or TB is the lack of a straightforward pathway for advanced development because of the absence of a robust correlate of protection. Such a correlate of immunity that associates with the incidence of infection is crucial to guide the development of vaccines, as it provides a way to down-select vaccine candidates that fail to induce the desired immune response. As such, correlates of protection serve as the fundamental "go/no-go" criterion to advance candidates through early stages of development. Current strategies to better define vaccine correlates of immunity are moving beyond the standard characterization of cellular and humoral responses to also analyze host and microbial genetic parameters using systematic OMICS-guided approaches. These novel strategies harness the power of "big data" for the purpose of identifying vaccine candidates that offer the best chance of providing protective immunity.
Effective vaccines for a number of human pathogens are lacking. In general, vaccines mimic natural protective immune responses. Thus, the improved ability to harness the native power of the human immune system and isolate pathogen-specific antibodies is helping to fill an important gap in vaccine development. Here we highlight the technological advances that have fast-tracked the discovery of new anti-infective monoclonal antibodies (mAbs). We discuss their role in a reverse vaccinology approach toward facilitating the design of better immunogens. We also review the development of mAbs as biological drugs to both prevent and treat infectious diseases. This chapter will focus mainly on human immunodeficiency virus type 1 and influenza virus but will also discuss other pathogens where significant progress has been made, as in the case of respiratory syncytial virus. These technologies are applicable across different diseases, providing a platform for tackling new or reemerging pathogens, such as Ebola viruses. The emergence and expansion of monoclonal antibody technologies herald a new era in the fight against infectious diseases.
Purpose of review To briefly describe some of the replication-competent vectors being investigated for development of candidate HIV vaccines focusing primarily on technologies that have advanced to testing in macaques or have entered clinical trials. Recent findings Replication-competent viral vectors have advanced to the stage at which decisions can be made regarding the future development of HIV vaccines. The viruses being used as replication-competent vector platforms vary considerably, and their unique attributes make it possible to test multiple vaccine design concepts and also mimic various aspects of an HIV infection. Replication-competent viral vectors encoding simian immunodeficiency virus or HIV proteins can be used to safely immunize macaques, and in some cases, there is evidence of significant vaccine efficacy in challenge protection studies. Several live HIV vaccine vectors are in clinical trials to evaluate immunogenicity, safety, the effect of mucosal delivery, and potential effects of preexisting immunity. Summary A variety of DNA and RNA viruses are being used to develop replication-competent viral vectors for HIV vaccine delivery. Multiple viral vector platforms have proven to be well tolerated and immunogenic with evidence of efficacy in macaques. Some of the more advanced HIV vaccine prototypes based on vesicular stomatitis virus, vaccinia virus, measles virus, and Sendai virus are in clinical trials.
Pneumococcal infections have a substantial burden in Turkey, particularly in the elderly (>60 years) and at-risk adults (18–59 years). VCR are low at approximately 2%. The first aim of this study was the evaluation of the burden of pneumococcal infections (pneumonia and bacteremia) from a public payer perspective in elderly and at-risk adults. The second aim was the evaluation of cost effectiveness of implementing a large PPV program in these populations. A decision tree model was employed using demographic and epidemiological input obtained from Turkish official sources and international literature. Vaccination was assumed to protect for 5 years with 60% and 50% effectiveness against BPP in elderly and at-risk adults respectively. Vaccination effectiveness of 21% against NBPP was assumed for both populations. Costs input were obtained from a previous study conducted between 2002 and 2008 in a public university hospital in Ankara, Turkey. Univariate sensitivity analyses and Monte-Carlo simulations were performed. The vaccination program was cost effective and cost saving compared to no vaccination, pneumococcal vaccination with 60% coverage led to a mean of 4,695 LYG in the elderly and 2,134 LYG in at-risk adults with 40% coverage. Mean incremental savings reached 45.4 million YTL in the elderly and 21.8 million YTL in at-risk adults. This analysis suggests that pneumococcal vaccination of elderly and at-risk adults is associated with a positive return on investment from a public payer perspective and supports the continued recommendation of pneumococcal vaccines, as well as their full funding in Turkey.
The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 μg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 μg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 years) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] <0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 years were immunologically non-inferior to the 3D schedule in women 15-25 years (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] <2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 years versus the 3D schedule in women 15-25 years. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 years and that the 2D schedule is likely adequate for younger females.
See Dr. Light original opinion peice in issue 7-2, along with links to related commentaries. http://www.landesbioscience.com/journals/vaccines/article/14919/
Aim: The lyophilized formulation of the human rotavirus vaccine, RIX4414 (RotarixTM), is recommended to be stored at 2°C–8°C for optimal immunogenicity. In some settings with inadequate infrastructure for vaccine storage, unforeseen circumstances may cause cold chain breakage, resulting in the vaccine to be left at ambient temperatures. This study evaluated the heat stability of lyophilized RIX4414 vaccine in terms of immunogenicity when stored at tropical room temperature (37°C) for 7 days before reconstitution.Results: There was no statistically significant difference detected between RIX4414 vaccine stored at 2°C–8°C (Group RIX4414_control, n = 171) and that stored at 37°C for 7 days (Group RIX4414_37°C, n = 47) in terms of seroconversion rate and vaccine take. The anti-rotavirus IgA seroconversion rate 2 months post-Dose 2 was 84.7% (95% CI: 78.1%–90%) and 87.8% (95% CI: 73.8%–95.9%) in Groups RIX4414_control and RIX4414_37°C, respectively. None of the 25 infants in placebo group seroconverted. The vaccine take in the respective vaccine groups were 88% (95% CI: 82.1%–92.5%) and 93.5% (95% CI: 82.1%–98.6%) and Geometric Mean Concentrations (GMCs) were 134.4 U/mL (95% CI: 104.5–172.9) and 163.7 U/mL (95% CI: 98.9–271.1).Methods: Healthy infants aged 6–12 weeks, received two oral doses of either the RIX4414 vaccine stored at 2°C–8°C, RIX4414 vaccine stored at 37°C for 7 days or placebo, according to a 0, 2 month schedule. Seroconversion rates in terms of anti-rotavirus IgA antibody levels (cut off: ≥20 U/mL by ELISA), anti-rotavirus IgA antibody GMCs and vaccine take were calculated 2 months post-Dose 2.Conclusion: Lyophilized RIX4414 vaccine stored at 37°C for 7 days before reconstitution has similar immunogenicity as the vaccine stored at 2°C–8°C. These results supported the use of RIX4414 in settings where the vaccine might be exposed to higher than the recommended storage temperatures.
Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. WHO has classified the disease as emerging and uncontrolled and estimates that the infection results in two million new cases a year. There are 12 million people currently infected worldwide, and leishmaniasis threatens 350 million people in 88 countries. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. However, to date, no such vaccine is available despite substantial efforts by many laboratories. Main obstacle in vaccine design is the transition from the laboratory to the field and extrapolation of data from animal models to humans. This review discusses recent findings in the antileishmania vaccine field and current difficulties hampering vaccine implementation.
Inactivated rotavirus vaccine is a safe and effective potential vaccine for the prevention of rotavirus infection among children, but no approved licensed vaccine is available now. In this study, a scalable inactivated rotavirus vaccine, prepared in Vero cells cultured by microcarrier fermentation, inactivated by formalin and absorbed by Al(OH)3 adjuvant, was vaccinated into the six weeks-old female Balb/c mice by intramuscular injection. After twice immunization at interval of three weeks, both humoral and cell-mediated immune responses were assessed by ELISA, microneutralization assay and EISPOT assay. The results indicated that the scalable inactivated rotavirus vaccines induced not only high serum IgG antibody and neutralizing antibody responses, but Th1 and Th2 cytokine-secreting cell responses in mice immunized by the inactivated rotavirus vaccines. These results suggest that the scalable inactivated rotavirus vaccine has good immunogenicity, which provided the base for the scaled development of inactivated rotavirus vaccine in the future.
The circumstances that in the opinion of the authors influence the lower than expected uptake of the vaccine against human papillomavirus in Spain are analyzed. Among others, aspects related to doubts about efficacy and safety, the attitude of the Spanish health authorities or the role of media and the antivaccine groups, as well as the vaccination "culture" of the gynecologist, are discussed. The authors conclude that only with the coordinated effort of all involved bodies in the vaccination process (health authorities, scientific societies, social agents, media...) wide coverage of HPV vaccine will be achieved.
We used site-directed mutagenesis to mutate two key amino acid residues, Glu164 and Arg167, of abrin A chain (ABRA), creating a mutant ABRAE164AR167L. The mutant ABRA (mABRA) encoded by mABRAE164AR167L was expressed in the cytoplasm of Escherichia coli, and used to develop an effective vaccine to protect mice against native abrin intoxication. The cytotoxicity of mABRA was dramatically reduced as compared to that of recombinant ABRA (rABRA) and native abrin, but the antigenicity and immunogenicity remained the same. Balb/c mice were vaccinated with purified mABRA, and survival was evaluated after challenge with native abrin. Mice that were given three vaccinations developed a protective immune response that was 100% protective against an intraperitoneal (i.p.) administration of 10×LD50 of native abrin. Furthermore, the sera from immunized mice provided complete passive protection for naive mice. This study describes the generation of a substantial amount of mABRA from E. coli and the potential application of mABRA as an effective vaccine candidate for humans, to protect against a high-dose of native abrin.
Objective To know the attitude towards seasonal influenza vaccination among healthcare worker (HCWs) and general community population (GCPs) in the post-pandemic influenza A/H1N1 period. Method We conducted a cross-sectional investigation in the beginning of seasonal influenza vaccination between 2010 and 2011, employed logistic regression analysis to compute the relationship between the willingness of seasonal influenza vaccination and variables after pandemic influenza A/H1N1. Results A total of 489 participants including 126 HCWs and 363 GCPs completed the investigation. 33.33% individuals (34.92% HCWs vs 32.78% GCPs, p＞0.05) intended to accept the seasonal influenza vaccination after pandemic influenza A/H1N1. Individuals received seasonal influenza vaccination in the prior 3 years and monovalent A/H1N1 vaccination in 2009 were aggressive to vaccinate seasonal influenza vaccine with adjusted OR= 5.21(3.20~8.49) and 1.97(1.18~3.30).. According to the results of multivariable logistic regression model, the safety not efficacy of influenza vaccine was the significant factor for acceptability of seasonal influenza vaccination (OR: 3.11, 95%CI: 1.76~5.50). The positive attitude of serious degree of influenza A/H1N1 and occupational factor were also associated with the willingness of seasonal influenza vaccination and the adjusted ORs were 2.09(1.14~3.83) and 1.62(1.00~2.64). Conclusion Participants showed low acceptability of seasonal influenza vaccination after pandemic influenza A/H1N1. Need educational program concerning the advantages of vaccine, comprehensible information about possible adverse effects and the hazards of seasonal influenza disease, which might motivate individuals to accept seasonal influenza vaccination.
At the beginning of 2010 DNA fragments of a porcine circovirus 1 (PCV-1) were detected in the monovalent rotavirus vaccine, Rotarix® (GlaxoSmithKline), and later also of PCV-1 and PCV-2 in the RotaTeq® (MSD) vaccine. These viruses are frequently found in meat and other products for normal human consumption and have not been shown to cause disease in humans. Although the World Health Organization (WHO) and the European Medicines Agency (EMA) did not recommended discontinuation of vaccination against rotavirus because of its positive risk- benefit ratio, the Spanish Medicines and Health Products Agency (AEMPS) did not authorize the release of new batches of Rotarix® and RotaTeq® vaccines onto the Spanish market since March 29 and June 10, 2010, respectively, due to problems of good manufacturing practice (GMP), until research on this issue was complete.1 On November 4, 2010, AEMPS again allowed the release of batches of the RotaTeq® vaccine having checked that it only had fragments of the DNA of the porcine virus (and thereby met the GMP standards), so that currently there are only restrictions on the marketing of the Rotarix® vaccine.1 Until March 2010, the average vaccination coverage against rotavirus in Spain in terms of dose distribution data (BMI and census data) had reached 40%. Furthermore, the first data reported on the effectiveness of the vaccine in Spain were consistent with this coverage and with the data reported for other countries.2,3
