Limited polymorphism in Plasmodium falciparum ookinete surface antigen, von Willebrand factor A domain-related protein from clinical isolates

BACKGROUND: As malaria becomes increasingly drug resistant and more costly to treat, there is increasing urgency to develop effective vaccines. In comparison to other stages of the malaria lifecycle, sexual stage antigens are under less immune selection pressure and hence are likely to have limited antigenic diversity. METHODS: Clinical isolates from a wide range of geographical regions were collected. Direct sequencing of PCR products was then used to determine the extent of polymorphisms for the novel Plasmodium falciparum sexual stage antigen von Willebrand Factor A domain-related Protein (PfWARP). These isolates were also used to confirm the extent of diversity of sexual stage antigen Pfs28. RESULTS: PfWARP was shown to have non-synonymous substitutions at 3 positions and Pfs28 was confirmed to have a single non-synonymous substitution as previously described. CONCLUSION: This study demonstrates the limited antigenic diversity of two prospective P. falciparum sexual stage antigens, PfWARP and Pfs28. This provides further encouragement for the proceeding with vaccine trials based on these antigens

Lyme disease in Wisconsin: epidemiologic, clinical, serologic, and entomologic findings.

In 1980-82, 80 individuals (71 Wisconsin residents) had confirmed Lyme disease (LD-c) reported; 39 additional patients had probable or possible LD. All cases of LD-c occurred during May-November; 73 percent occurred during June-July; 54 (68 percent) occurred in males. The mean age was 38.7 years (range, 7-77 years). Among LD-c patients, likely exposure to the presumed vector Ixodes dammini (ID) occurred in 22 different Wisconsin counties. Antibodies to the ID spirochete that causes LD occurred in 33 of 49 LD-c cases versus 0 of 18 in ill controls (p less than .001) and in 13 of 26 LD-c cases treated with penicillin or tetracycline versus 16 of 19 LD-c cases not treated. Early antibiotic therapy appears to blunt the antibody response to the ID spirochete. Regional tick surveys conducted in Wisconsin during each November in 1979-82 have demonstrated regions of greater density of ID. Utilizing comparable tick collection in these surveys, increases were noted in the percentage of deer with ID from 24 percent (31/128) in 1979 to 38 percent (58/152) in 1981, in the standardized mean value of ID/deer from 1.0 in 1979 to 2.2 in 1981, in the percentage of ID of the total ticks collected from 13 percent in 1979 to 71 percent in 1981, or in the ratio of ID to Dermacentor albipictus ticks from 0.14 in 1979 to 2.44 in 1981. However, a reduction in the density of ID/deer was noted generally throughout Wisconsin in 1982 when compared to 1981. LD is widespread in Wisconsin, with ecologic and clinical features similar to those occurring along the eastern seaboard

WHO consultation on group B Streptococcus vaccine development: Report from a meeting held on 27-28 April 2016.

Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection

Evolution, revolution and heresy in the genetics of infectious disease susceptibility

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference

Recombination rate and selection strength in HIV intra-patient evolution

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Here, we estimate the rate of recombination and the distribution of selection coefficients from time-resolved sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be r=1.4e-5 recombinations per site and generation. Furthermore, we provide evidence that selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible, as soon as data with higher time resolution and greater sample sizes is available.Comment: to appear in PLoS Computational Biolog

The illusion of competency versus the desirability of expertise: Seeking a common standard for support professions in sport

In this paper we examine and challenge the competency-based models which currently dominate accreditation and development systems in sport support disciplines, largely the sciences and coaching. Through consideration of exemplar shortcomings, the limitations of competency-based systems are presented as failing to cater for the complexity of decision making and the need for proactive experimentation essential to effective practice. To provide a better fit with the challenges of the various disciplines in their work with performers, an alternative approach is presented which focuses on the promotion, evaluation and elaboration of expertise. Such an approach resonates with important characteristics of professions, whilst also providing for the essential ‘shades of grey’ inherent in work with human participants. Key differences between the approaches are considered through exemplars of evaluation processes. The expertise-focused method, although inherently more complex, is seen as offering a less ambiguous and more positive route, both through more accurate representation of essential professional competence and through facilitation of future growth in proficiency and evolution of expertise in practice. Examples from the literature are also presented, offering further support for the practicalities of this approach

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects.

BACKGROUND: VCL-CB01, a candidate cytomegalovirus (CMV) DNA vaccine that contains plasmids encoding CMV phosphoprotein 65 (pp65) and glycoprotein B (gB) to induce cellular and humoral immune responses and that is formulated with poloxamer CRL1005 and benzalkonium chloride to enhance immune responses, was evaluated in a phase 1 clinical trial. METHODS: VCL-CB01 was evaluated in 44 healthy adult subjects (22 CMV seronegative and 22 CMV seropositive) 18-43 years old. Thirty-two subjects received 1- or 5-mg doses of vaccine on a 0-, 2-, and 8-week schedule, and 12 subjects received 5-mg doses of vaccine on a 0-, 3-, 7-, and 28-day schedule. RESULTS: Overall, the vaccine was well tolerated, with no serious adverse events. Local reactions included mild to moderate injection site pain and tenderness, induration, and erythema. Systemic reactions included mild to moderate malaise and myalgia. All reactions resolved without sequelae. Through week 16 of the study, immunogenicity, as measured by enzyme-linked immunosorbant assay and/or ex vivo interferon (IFN)-gamma enzyme-linked immunospot assay, was documented in 45.5% of CMV-seronegative subjects and in 25.0% of CMV-seropositive subjects who received the full vaccine series, and 68.1% of CMV-seronegative subjects had memory IFN-gamma T cell responses at week 32. CONCLUSION: The safety and immunogenicity data from this trial support further evaluation of VCL-CB01

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary