Impact Vaccine Efficacy Research Articles

Comparative analysis of the RVA VP7 and VP4 antigenic epitopes circulating in Iran and the Rotarix and RotaTeq vaccines

Analyzing the lineages and detecting antigenic variation in immunogenic motifs of Group A Rotavirus (RVA) variants is crucial because it can impact vaccine efficacy. This study investigated the circulating lineages of VP4 and VP7 proteins of human RVA isolates and their phylogeny in ≤24-month-old symptomatic, rotavirus-positive children with transudative diarrhea within 48 h of admission to Mofid Children's Hospital between December 2020 and March 2022 in Tehran, Iran. Antigen detection was performed by ELISA, RNA extraction, and semi-nested multiplex PCR for G/P genotypes, followed by sequencing and bioinformatic analysis using multiple sequence alignments in MEGA and phylogenetic analysis by Geneious Prime. The similarity of VP7 and VP4 amino acids with the RotaTeq and Rotarix vaccine strains for cytotoxic T cell and antigenic epitopes was evaluated using the UCSF Chimera Molecular Modeling System. Overall, 27.3 % of the samples were RVA positive, showing untypeable (2.5 %), single (76.9 %), and mixed (20.5 %) genotypic characteristics. The strains clustered in the G1/II, G2/IV, G3/I, G4/I, G9/III, P[8]/III, P[4]/V, and P[6]/I lineages. Comparative analysis of VP7 antigenic epitopes showed that the G1/II strains were completely conserved, while the G2/IV, G3/I, G4/I, G6, G9/III strains contained 2, 3–5, 2, 4 and 9 amino acid substitutions, respectively. The P[8]/III genotypes differed by 3 amino acids, while the P[6]/I genotype had the most substitutions. CTL epitopes were completely conserved in G3/I strains, but other genotypes differed by 1–4 amino acids compared to the vaccine strains. Given the diversity of circulating RVA genotypes and the observed mutations in neutralizing and CTL epitopes, immune escape by some of the strains is likely in Iran. This finding underscores the importance of evaluating the effect of rotavirus vaccines on local genotypes and related lineages before implementing a vaccination program.

Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population.

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Molecular characterization of canine parvovirus type 2 (CPV2) reveals a high prevalence of the CPV2c genotype among dogs suffering from diarrhea

AbstractCanine parvovirus 2 (CPV-2) is a highly contagious virus in dogs that typically causes hemorrhagic enteritis and a high mortality rate in unvaccinated puppies. The genetic variability and antigenic diversity of CPV-2 hinder its effective prevention of infection by vaccination. To investigate the epidemiology and genetic characteristics of CPV-2 in China, rectal swabs from affected dogs were collected from different animal clinics in Kunshan from 2022 to 2023. Preliminary detection and capsid gene sequencing of CPV-2 were performed using previously described primers and protocols. The overall detection rate for CPV-2 was 16.5% (33/200). A significant association was found between the CPV-2-positivity and clinical signs, age, breed and vaccination status. Sequence analysis revealed the presence of CPV-2c genotypes in all positive samples, which were genetically similar to other Asian CPV-2c strains. Notably, four key mutations (A5G, F267Y, Y324I and Q370R) were detected in all isolates, and one novel mutation (I447M) was detected in three CPV-2 isolates. These mutations in the CPV-2 strains could impact vaccine efficacy and the effectiveness of the virus immune evasion. Surprisingly, no recombination events were observed between the identified CPV-2c strains and reference strains from China. Our data revealed that amino acid residues 324, 426 and 440 of VP2 may under strong selection pressure. This pattern of genetic variation in the CPV-2 lineage warrants continuous laboratory-based surveillance programs in other parts of China to better understand the pattern of seasonal distribution and association between emerging genotypes and the intensity of disease severity.

Differential Genome Replication of a Unique Single-Amino-Acid Mutation in the Adenovirus-4 Component of the Live Oral Adenovirus Type 4 and Type 7 Vaccine.

The FDA-approved Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is highly effective and essential in preventing acute respiratory diseases (ARDs) in U.S. military recruits. Our study revealed the presence of a previously undetected mutation, not found in the wild-type human adenovirus type 4 (HAdV-4) component of the licensed vaccine, which contains an amino acid substitution (P388T) in the pre-terminal protein (pTP). This study demonstrated that replication of the T388 HAdV-4 vaccine mutant virus is favored over the wild type in WI-38 cells, the cell type utilized in vaccine manufacturing. However, results from serial human stool specimens of vaccine recipients support differential genome replication in the gastrointestinal tract (GI), demonstrated by the steady decline of the percentage of mutant T388 vaccine virus. Since vaccine efficacy depends upon GI replication and the subsequent immune response, the mutation can potentially impact vaccine efficacy.

Short-Chain Fatty Acids Alleviate Vancomycin-Caused Humoral Immunity Attenuation in Rabies-Vaccinated Mice by Promoting the Generation of Plasma Cells via Akt-mTOR Pathway.

Mounting evidence suggests that gut microbial composition and its metabolites, including short-chain fatty acids (SCFAs), have beneficial effects in regulating host immunogenicity to vaccines. However, it remains unknown whether and how SCFAs improve the immunogenicity of the rabies vaccine. In this study, we investigated the effect of SCFAs on the immune response to rabies vaccine in vancomycin (Vanco)-treated mice and found that oral gavage with butyrate-producing bacteria (C. butyricum) and butyrate supplementation elevated RABV-specific IgM, IgG, and virus-neutralizing antibodies (VNAs) in Vanco-treated mice. Supplementation with butyrate expanded antigen-specific CD4+ T cells and IFN-γ-secreting cells, augmented germinal center (GC) B cell recruitment, promoted plasma cells (PCs) and RABV-specific antibody-secreting cells (ASCs) generation in Vanco-treated mice. Mechanistically, butyrate enhanced mitochondrial function and activated the Akt-mTOR pathway in primary B cells isolated from Vanco-treated mice, ultimately promoting B lymphocyte-induced maturation protein-1 (Blimp-1) expression and CD138+ PCs generation. These results highlight the important role of butyrate in alleviating Vanco-caused humoral immunity attenuation in rabies-vaccinated mice and maintaining host immune homeostasis. IMPORTANCE The gut microbiome plays many crucial roles in the maintenance of immune homeostasis. Alteration of the gut microbiome and metabolites has been shown to impact vaccine efficacy. SCFAs can act as an energy source for B-cells, thereby promoting both mucosal and systemic immunity in the host by inhibiting HDACs and activation of GPR receptors. This study investigates the impact of orally administered butyrate, an SCFA, on the immunogenicity of rabies vaccines in Vanco-treated mice. The results showed that butyrate ameliorated humoral immunity by facilitating the generation of plasma cells via the Akt-mTOR in Vanco-treated mice. These findings unveil the impact of SCFAs on the immune response of the rabies vaccine and confirm the crucial role of butyrate in regulating immunogenicity to rabies vaccines in antibiotic-treated mice. This study provides a fresh insight into the relationship of microbial metabolites and rabies vaccination.

Tilapia Lake Virus Vaccine Development: A Review on the Recent Advances.

Tilapia tilapinevirus (or tilapia lake virus, TiLV) is a recently emerging virus associated with a novel disease affecting and decimating tilapia populations around the world. Since its initial identification, TiLV has been reported in 17 countries, often causing mortalities as high as 90% in the affected populations. To date, no therapeutics or commercial vaccines exist for TiLV disease control. Tilapia exposed to TiLV can develop protective immunity, suggesting that vaccination is achievable. Given the important role of vaccination in fish farming, several vaccine strategies are currently being explored and put forward against TiLV but, a comprehensive overview on the efficacy of these platforms is lacking. We here present these approaches in relation with previously developed fish vaccines and discuss their efficacy, vaccine administration routes, and the various factors that can impact vaccine efficacy. The overall recent advances in TiLV vaccine development show different but promising levels of protection. The field is however hampered by the lack of knowledge of the biology of TiLV, notably the function of its genes. Further research and the incorporation of several approaches including prime-boost vaccine regimens, codon optimization, or reverse vaccinology would be beneficial to increase the effectiveness of vaccines targeting TiLV and are further discussed in this review.

Development of a COVID-19 Vaccine Readiness Kit for Veterans With Rheumatologic Diseases on Immunomodulators: A Quality Improvement Project.

The advent of multiple safe and effective vaccines to prevent SARS-CoV-2 infection represents a major step in resolving the COVID-19 global pandemic. Vaccination of individuals with rheumatologic diseases on immunomodulators represents an additional challenge because data suggest that certain immunomodulators may impact vaccine efficacy. At a large, predominantly rural Midwestern Veterans Affairs rheumatology clinic, an interprofessional group of investigators conducted a quality improvement project to develop a COVID-19 vaccine readiness kit, consisting of patient education materials and a readiness questionnaire to help guide veteran decision-making. Using a Lean Six Sigma approach and the DMAIC (Define-Measure-Analyze-Improve-Control) framework, the investigators identified customer values, needs, and barriers to participation. Return rates and responses from the questionnaire were tracked over 28 days. One hundred seventy-nine veterans were identified and mailed kits; 129 (73%) returned the questionnaire within 28 days. Ninety-seven percent of those opted to hold immunomodulators after at least 1 administration of the vaccine; 3.1% were not interested in vaccination. Veterans voiced satisfaction at the simplicity of the process, comprehensibility of materials, and the clarity of communication. The Lean Six Sigma approach, systematically focusing on identifying the values, needs, and barriers of veterans on immunomodulators, was critical to high participation rates from veterans. This approach is cost-effective for resource-poor settings, audiences without access or familiarity to digital content, and rural settings separated by large geographic distances.

Quantitative SARS-CoV-2 anti-spike responses to Pfizer–BioNTech and Oxford–AstraZeneca vaccines by previous infection status

ObjectivesWe investigated determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike IgG responses in healthcare workers (HCWs) following one or two doses of Pfizer–BioNTech or Oxford–AstraZeneca vaccines. MethodsHCWs participating in regular SARS-CoV-2 PCR and antibody testing were invited for serological testing prior to first and second vaccination, and 4 weeks post-vaccination if receiving a 12-week dosing interval. Quantitative post-vaccination anti-spike antibody responses were measured using the Abbott SARS-CoV-2 IgG II Quant assay (detection threshold: ≥50 AU/mL). We used multivariable logistic regression to identify predictors of seropositivity and generalized additive models to track antibody responses over time. Results3570/3610 HCWs (98.9%) were seropositive >14 days post first vaccination and prior to second vaccination: 2706/2720 (99.5%) were seropositive after the Pfizer–BioNTech and 864/890 (97.1%) following the Oxford–AstraZeneca vaccines. Previously infected and younger HCWs were more likely to test seropositive post first vaccination, with no evidence of differences by sex or ethnicity. All 470 HCWs tested >14 days after the second vaccination were seropositive. Quantitative antibody responses were higher after previous infection: median (IQR) >21 days post first Pfizer–BioNTech 14 604 (7644–22 291) AU/mL versus 1028 (564–1985) AU/mL without prior infection (p < 0.001). Oxford–AstraZeneca vaccine recipients had lower readings post first dose than Pfizer–BioNTech recipients, with and without previous infection, 10 095 (5354–17 096) and 435 (203–962) AU/mL respectively (both p < 0.001 versus Pfizer–BioNTech). Antibody responses >21 days post second Pfizer vaccination in those not previously infected, 10 058 (6408–15 582) AU/mL, were similar to those after prior infection followed by one vaccine dose. ConclusionsSARS-CoV-2 vaccination leads to detectable anti-spike antibodies in nearly all adult HCWs. Whether differences in response impact vaccine efficacy needs further study.

Stability of Outer Membrane Vesicles-Based Vaccines, Identifying the Most Appropriate Methods to Detect Changes in Vaccine Potency.

Ensuring the stability of vaccines is crucial to successfully performing global immunization programs. Outer Membrane Vesicles (OMV) are receiving great attention as vaccine platforms. OMV are complex molecules and few data have been collected so far on their stability. OMV produced by bacteria, genetically modified to increase their spontaneous release, simplifying their production, are also known as Generalized Modules for Membrane Antigens (GMMA). We have performed accelerated stability studies on GMMA from different pathogens and verified the ability of physico-chemical and immunological methods to detect possible changes. High-temperature conditions (100 °C for 40 min) did not affect GMMA stability and immunogenicity in mice, in contrast to the effect of milder temperatures for a longer period of time (37 °C or 50 °C for 4 weeks). We identified critical quality attributes to monitor during stability assessment that could impact vaccine efficacy. In particular, specific recognition of antigens by monoclonal antibodies through competitive ELISA assays may replace in vivo tests for the potency assessment of GMMA-based vaccines.

The Effects of Pre-Existing Antibodies on Live-Attenuated Viral Vaccines.

Live-attenuated vaccines (LAVs) have achieved remarkable successes in controlling virus spread, as well as for other applications such as cancer immunotherapy. However, with rapid increases in international travel, globalization, geographic spread of viral vectors, and widespread use of vaccines, there is an increasing need to consider how pre-exposure to viruses which share similar antigenic regions can impact vaccine efficacy. Pre-existing antibodies, derived from either from maternal–fetal transmission, or by previous infection or vaccination, have been demonstrated to interfere with vaccine immunogenicity of measles, adenovirus, and influenza LAVs. Immune interference of LAVs can be caused by the formation of virus–antibody complexes that neutralize virus infection in antigen-presenting cells, or by the cross-linking of the B-cell receptor with the inhibitory receptor, FcγRIIB. On the other hand, pre-existing antibodies can augment flaviviral LAV efficacy such as that of dengue and yellow fever virus, especially when pre-existing antibodies are present at sub-neutralizing levels. The increased vaccine immunogenicity can be facilitated by antibody-dependent enhancement of virus infection, enhancing virus uptake in antigen-presenting cells, and robust induction of innate immune responses that promote vaccine immunogenicity. This review examines the literature on this topic and examines the circumstances where pre-existing antibodies can inhibit or enhance LAV efficacy. A better knowledge of the underlying mechanisms involved could allow us to better manage immunization in seropositive individuals and even identify possibilities that could allow us to exploit pre-existing antibodies to boost vaccine-induced responses for improved vaccine efficacy.

Influenza vaccines using liposomal formulations of toll-like receptor (TLR) 7/8 and 4 agonists as adjuvants

Abstract Influenza virus infection is a global health concern and causes severe illness and thousands of deaths each year. While there are currently licensed vaccines available for both seasonal and pandemic influenza viruses there are several issues to consider; 1) current vaccines do not provide supra-seasonal or universal protection against influenza subtypes, 2) antigenic mismatch between the vaccine and circulating influenza strains impact vaccine efficacy, 3) and the efficacy of influenza seasonal vaccines could be improved in the elderly and immune compromised populations. Therefore, vaccine adjuvants capable of inducing more robust and broadly cross-protective immune responses to various subtypes of influenza virus is a critical unmet need. To address this challenge, we developed a synthetic dual TLR adjuvant combination system (TRAC-478) to improve influenza vaccine immunity. Preliminary data in human peripheral blood mononuclear cells demonstrate that combining our synthetic TLR7/8 and TLR4 agonists results in a synergistic innate immune responses. Influenza vaccine immunogenicity studies in both murine and pig models demonstrate the safety and efficacy of this new dual TLR adjuvant system. Using a co-encapsulated TRAC-478 liposome delivery system with a split-flu vaccine resulted in strong anti-influenza humoral, Th1 cell mediated immunity, and protection from a heterologous influenza challenge in mice. We hypothesize that using the TRAC-478 adjuvant system in combination with current influenza vaccines will induce a more robust and broadly cross-protective immune responses to circulating or pandemic influenza virus.

Host Factors Impact Vaccine Efficacy: Implications for Seasonal and Universal Influenza Vaccine Programs.

Influenza is a global public health problem. Current seasonal influenza vaccines have highly variable efficacy, and thus attempts to develop broadly protective universal influenza vaccines with durable protection are under way. While much attention is given to the virus-related factors contributing to inconsistent vaccine responses, host-associated factors are often neglected. Growing evidences suggest that host factors including age, biological sex, pregnancy, and immune history play important roles as modifiers of influenza virus vaccine efficacy. We hypothesize that host genetics, the hormonal milieu, and gut microbiota contribute to host-related differences in influenza virus vaccine efficacy. This review highlights the current insights and future perspectives into host-specific factors that impact influenza vaccine-induced immunity and protection. Consideration of the host factors that affect influenza vaccine-induced immunity might improve influenza vaccines by providing empirical evidence for optimizing or even personalizing vaccine type, dose, and use of adjuvants for current seasonal and future universal influenza vaccines.

Transcriptomic differences noted in Glaesserella parasuis between growth in broth and on agar.

Glaesserella parasuis is the cause of Glӓsser’s disease in pigs and is a significant contributor to post-weaning mortality in the swine industry. Prevention of G. parasuis disease relies primarily on bacterin vaccines, which have shown good homologous protection and variable heterologous protection. Bacterin production involves large scale growth of the bacteria and proteins produced during the proliferation phase of production become important antigens that stimulate the immune response. In order to evaluate genes activated during G. parasuis growth on different media substrates, the transcriptome of broth and agar grown G. parasuis strain 29755 were sequenced and compared. The transcription of most purported virulence genes were comparable between broth and agar grown G. parasuis; however, four virulence-associated genes, including ompA and vapD, had elevated expression under agar growth, while six virulence-associate genes had elevated expression during broth growth, including several protease genes. Additionally, there were metabolic shifts toward increased protein and lipid production and increased cellular division in broth grown G. parasuis. The results contribute to the understanding of how growth substrate alters gene transcription and protein expression, which may impact vaccine efficacy if immunogens important to the protective immune response are not produced under specific in vitro conditions. While the results of this work are unable to fully elucidate which growth medium presents a transcriptome more representative of in vivo samples or best suited for bacterin production, it forms a foundation that can be used for future comparisons and provides a better understanding of the metabolic differences in broth and agar grown bacteria.

Increasing FIM2/3 antigen-content improves efficacy of Bordetella pertussis vaccines in mice in vivo without altering vaccine-induced human reactogenicity biomarkers in vitro

Current acellular-pertussis (aP) vaccines appear inadequate for long-term pertussis control because of short-lived efficacy and the increasing prevalence of pertactin-negative isolates which may negatively impact vaccine efficacy. In this study, we added fimbriae (FIM)2 and FIM3 protein to licensed 2-, 3- or 5-component aP vaccines (Pentavac®, Boostrix®, Adacel®, respectively) to assess whether an aP vaccine with enhanced FIM content demonstrates enhanced efficacy. Vaccine-induced protection was assessed in an intranasal mouse challenge model. In addition, potential reactogenicity was measured by biomarkers in a human whole blood assay (WBA) in vitro and benchmarked the responses against licensed whole cell pertussis (wP) and aP vaccines including Easyfive®, Pentavac® and Pentacel®. The results show that commercial vaccines demonstrated reduced efficacy against pertactin-negative versus pertactin-positive strains. However, addition of higher amounts of FIM2/3 to aP vaccines reduced lung colonization and increased vaccine efficacy against a pertactin-negative strain in a dose-dependent manner. Improvements in efficacy were similar for FIM2 and FIM3-expressing strains. Increasing the amount of FIM2/3 proteins in aP formulations did not alter vaccine-induced biomarkers of potential reactogenicity including prostaglandin E2, cytokines and chemokines in human newborn cord and adult peripheral blood tested in vitro. These results suggest that increasing the quantity of FIM proteins in current pertussis vaccine formulations may further enhance vaccine efficacy against B. pertussis infection without increasing the reactogenicity of the vaccine.

Histo-Blood Group Antigen Phenotype Determines Susceptibility to Genotype-Specific Rotavirus Infections and Impacts Measures of Rotavirus Vaccine Efficacy.

BackgroundLewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE.MethodsIn infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD.ResultsA vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort.ConclusionsHost HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status.Clinical Trials RegistrationNCT01375647.

HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates.

A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.

Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.

The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.

Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered by In Vivo Electroporation in Preclinical Studies in Mice

Plasmodium falciparum sexual stage surface antigen Pfs25 is a well-established candidate for malaria transmission-blocking vaccine development. Immunization with DNA vaccines encoding Pfs25 has been shown to elicit potent antibody responses in mice and nonhuman primates. Studies aimed at further optimization have revealed improved immunogenicity through the application of in vivo electroporation and by using a heterologous prime-boost approach. The goal of the studies reported here was to systematically evaluate the impact of codon optimization, in vivo electroporation, and N-linked glycosylation on the immunogenicity of Pfs25 encoded by DNA vaccines. The results from this study demonstrate that while codon optimization and in vivo electroporation greatly improved functional immunogenicity of Pfs25 DNA vaccines, the presence or absence of N-linked glycosylation did not significantly impact vaccine efficacy. These findings suggest that N-glycosylation of Pfs25 encoded by DNA vaccines is not detrimental to overall transmission-blocking efficacy.

Schistosoma mansoni soluble egg antigens enhance T cell responses to a newly identified HIV-1 Gag H-2b epitope.

Schistosome infection induces significant T helper type 2 (Th2) and anti-inflammatory immune responses and has been shown to negatively impact vaccine efficacy. Our goal was to determine if the administration of schistosome soluble egg antigens (SEA) would negatively influence the induction of cytotoxic T lymphocyte (CTL) and Th1-type T cell responses to an HIV candidate vaccine in the Th1-biased C57BL/6 mouse strain. Initial experiments failed, as we were unable to detect any response to the defined class I epitope for HIV-1 IIIB Gag. Therefore, we initiated an epitope mapping study to identify C57BL/6 (H-2(b)) T cell epitopes in HIV-1 IIIB Gag in order to perform the experiments. This analysis defined two previously unreported minimal class I H-2(b) and class II I-A(b) epitopes for HIV-1 IIIB Gag. The newly defined HIV-1 IIIB Gag epitopes were used to evaluate the influence of SEA on the generation of CTL and Th1-type HIV-1 IIIB Gag responses. Surprisingly, in contrast to our hypothesis, we observed that the coadministration of SEA with a Listeria monocytogenes vector expressing HIV-1 IIIB Gag (Lm-Gag) led to a significantly increased frequency of gamma interferon (IFN-γ)-producing CD8(+) and CD4(+) T cells in C57BL/6 mice compared to mice immunized with Lm-Gag only. These observations suggest that SEA contains, in addition to Th2-type and immune-suppressive molecules, substances that can act with the Lm-Gag vaccine to increase CTL and Th1-type vaccine-specific immune responses.

Immunology of infants through adolescents: responses to emulate for HIV vaccines

The major target groups for an HIV vaccine include breastfeeding infants and adolescents. Differential immune maturity in these age groups may significantly impact vaccine efficacy, and should be taken into account when developing vaccines. Here we review these differences, with an emphasis on the immune response to vaccines for HIV and other pathogens. Recommendations for potential adaptation of current HIV vaccines are also made. An effective neonatal vaccine needs to be immunogenic in the presence of maternal antibody, and must induce cytotoxic T-lymphocyte responses, neutralizing antibody responses, both systemic and mucosal. There is renewed hope in the possibility of stimulating neutralizing antibodies with HIV vaccination. DNA vaccines are promising for neonates, but will need appropriate boosting. Certain adjuvants and vector delivery systems are more suitable for neonates. Adolescents may have stronger immune responses to HIV vaccines than adults, and will also require induction of mucosal neutralizing humoral and cellular immunity. Some current HIV vaccine strategies may need adaptation for neonates and suitable product development should be accelerated. Vaccines could induce better responses in adolescents and therefore should not be discarded prematurely. Development of vaccines that have potential for these age groups is an urgent global priority.