Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose.

As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1-66.7) to 96.3% (95% CI, 94.2-98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2-90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months.

BACKGROUND: Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. METHODS: We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. RESULTS: The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). CONCLUSIONS: Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers.

BACKGROUND: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity. METHODS: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity. RESULTS: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented. CONCLUSIONS: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

Sounds of danger and post-traumatic stress responses in wild rodents: ecological validity of a translational model of post-traumatic stress disorder.

In the wild, animals face a highly variable world full of predators. Most predator attacks are unsuccessful, and the prey survives. According to the conventional perspective, the fear responses elicited by predators are acute and transient in nature. However, the long-term, non-lethal effects of predator exposure on prey behavioral stress sequelae, such as anxiety and post-traumatic symptoms, remain poorly understood. Most experiments on animal models of anxiety-related behavior or post-traumatic stress disorder have been carried out using commercial strains of rats and mice. A fundamental question is whether laboratory rodents appropriately express the behavioral responses of wild species in their natural environment; in other words, whether behavioral responses to stress observed in the laboratory can be generalized to natural behavior. To further elucidate the relative contributions of the natural selection pressures influences, this study investigated the bio-behavioral and morphological effects of auditory predator cues (owl territorial calls) in males and females of three wild rodent species in a laboratory set-up: Acomys cahirinus; Gerbillus henleyi; and Gerbillus gerbillus. Our results indicate that owl territorial calls elicited not only "fight or flight" behavioral responses but caused PTSD-like behavioral responses in wild rodents that have never encountered owls in nature and could cause, in some individuals, enduring physiological and morphological responses that parallel those seen in laboratory rodents or traumatized people. In all rodent species, the PTSD phenotype was characterized by a blunting of fecal cortisol metabolite response early after exposure and by a lower hypothalamic orexin-A level and lower total dendritic length and number in the dentate gyrus granule cells eight days after predator exposure. Phenotypically, this refers to a significant functional impairment that could affect reproduction and survival and thus fitness and population dynamics.

Early Immunogenicity and Safety of the Third Dose of BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine Among Adults Older Than 60 Years: Real-World Experience.

BACKGROUND: Despite high vaccine coverage, an increase in breakthrough coronavirus disease 2019 (COVID-19) infections, prompted administration of a third BNT162b2 dose to people aged >60 years in Israel since July 2021. Here, we report real-world immunogenicity following third dose. METHODS: Overall, 208 healthcare workers aged >60 years were included. Paired pre- and post-second and/or third dose immunoglobulin G (IgG) and neutralizing antibody titers were compared. A subpopulation of low responders to the second dose was also tested for T-cell activation. For 25 paired serum samples, we tested neutralization of wild-type vs neutralization of Delta and Lambda variants, pre- and post-third dose. Active surveillance of vaccine adverse events was conducted through surveys. RESULTS: A pronounced immune response was observed following the third dose, including a 33-fold and 51-fold increase in IgG and neutralizing antibody, respectively. The neutralizing antibody levels post-third dose were 9.34 times higher than post-second dose (geometric mean titer, 2598 [95% confidence interval {CI}, 2085-3237] vs 207 [95% CI, 126-339]). Nine previously low responders had a significant antibody increase post-third dose, and 7 of 9 showed increase in T-cell activation. Additionally, sera obtained post-third dose highly and comparably neutralized the wild-type and Delta and Lambda variants. Of 1056 responders to the adverse-event survey, none had serious events. CONCLUSIONS: We demonstrate a rapid and broad immune response to the third BNT162b2 dose in individuals >60 years of age.

Existence of immunological memory response in true sero-negative individuals post COVID-19 molecular diagnosis.

Approximately 1-8% of individuals do not develop antibodies following SARS-CoV-2 infection (sero-negatives). One BNT162b2 dose resulted in potent humoral response in 14 sero-negatives and 15 sero-positives, significantly higher than the response of 15 naïve-individuals, to two doses suggesting that COVID-19 provoked a memory response in individuals without detectable antibodies.

The dilution effect behind the scenes: testing the underlying assumptions of its mechanisms through quantifying the long-term dynamics and effects of a pathogen in multiple host species.

Disentangling the mechanisms that mediate the relationships between species diversity and disease risk has both theoretical and applied implications. We employed a model system of rodents and their Mycoplasma pathogens, in which an extreme negative diversity-disease relationship was demonstrated, to test the assumptions underlying three mechanisms that may explain this field pattern. Through quantifying the long-term dynamics and effects of the pathogen in its three host species, we estimated the between-host differences in pathogen spreading and transmission potentials, and host recovery potential and vulnerability to infection. The results suggest that one of the hosts is a pathogen amplifier and the other two hosts function as diluters. Considering the similarity in infection success and intensity among hosts, and the failure to detect any pathogen-induced damage, we could not validate the assumption underlying the hypotheses that diluters reduce the overall transmission or increase the mortality of infected hosts in the system. Instead, the results demonstrate that diluters clear the infection faster than amplifiers, supporting the possibility that the addition of diluters to the community may reduce the overall number of infected hosts through this mechanism. This study highlights the contribution of experimental studies that simultaneously explore different aspects of host-pathogen interactions in multiple hosts, in diversity-disease research.

SARS-CoV-2 outbreak in a synagogue community: longevity and strength of anti-SARS-CoV-2 IgG responses.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic is still ongoing along with the global vaccination efforts against it. Here, we aimed to understand the longevity and strength of anti-SARS-CoV-2 IgG responses in a small community (n = 283) six months following local SARS-COV-2 outbreak in March 2020. Three serological assays were compared and neutralisation capability was also determined. Overall 16.6% (47/283) of the participants were seropositive and 89.4% (42/47) of the IgG positives had neutralising antibodies. Most of the symptomatic individuals confirmed as polymerase chain reaction (PCR) positive during the outbreak were seropositive (30/32, 93.8%) and 33.3% of the individuals who quarantined with a PCR confirmed patient had antibodies. Serological assays comparison revealed that Architect (Abbott) targeting the N protein LIASON® (DiaSorin) targeting the S protein and enzyme-linked immunosorbent assay (ELISA) targeting receptor binding domain detected 9.5% (27/283), 17.3% (49/283) and 17% (48/283), respectively, as IgG positives. The latter two assays highly agreed (kappa = 0.89) between each other. In addition, 95%, (19/20, by ELISA) and 90.9% (20/22, with LIASON) and only 71.4% (15/21, by Architect) of individuals that were seropositive in May 2020 were found positive also in September. The unexpected low rate of overall immunity indicates the absence of un-noticed, asymptomatic infections. Lack of overall high correlation between the assays is attributed mainly to target-mediated antibody responses and suggests that using a single serological assay may be misleading.

Immunoglobulin (Ig)A seropositivity against SARS-CoV-2 in healthcare workers in Israel, 4 April to 13 July 2020: an observational study.

IntroductionThe COVID-19 pandemic has put healthcare workers (HCW) at significant risk. Presence of antibodies can confirm prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.AimThis study investigates the prevalence of IgA and IgG antibodies against SARS-CoV-2 in HCW.MethodsPerformance of IgA and IgG antibody ELISA assays were initially evaluated in positive and negative SARS-CoV-2 serum samples. IgA and IgG antibodies against SARS-CoV-2 were measured in 428 asymptomatic HCW. We assessed the risk of two groups: HCW with high exposure risk outside work (HROW) residing in areas where COVID-19 was endemic (n = 162) and HCW with high exposure risk at work (HRAW) in a COVID-19 intensive care unit (ICU) (n = 97).ResultsSensitivities of 80% and 81.2% and specificities of 97.2% and 98% were observed for IgA and IgG antibodies, respectively. Of the 428 HCW, three were positive for IgG and 27 for IgA. Only 3/27 (11%) IgA-positive HCW had IgG antibodies compared with 50/62 (81%) in a group of previous SARS-CoV-2-PCR-positive individuals. Consecutive samples from IgA-positive HCW demonstrated IgA persistence 18-83 days in 12/20 samples and IgG seroconversion in 1/20 samples. IgA antibodies were present in 8.6% of HROW and 2% of HRAW.ConclusionsSARS-CoV-2 exposure may lead to asymptomatic transient IgA response without IgG seroconversion. The significance of these findings needs further study. Out of work exposure is a possible risk of SARS-CoV-2 infection in HCW and infection in HCW can be controlled if adequate protective equipment is implemented.

The dynamics between limited-term and lifelong coinfecting bacterial parasites in wild rodent hosts.

Interactions between coinfecting parasites may take various forms, either direct or indirect, facilitative or competitive, and may be mediated by either bottom-up or top-down mechanisms. Although each form of interaction leads to different evolutionary and ecological outcomes, it is challenging to tease them apart throughout the infection period. To establish the first step towards a mechanistic understanding of the interactions between coinfecting limited-term bacterial parasites and lifelong bacterial parasites, we studied the coinfection of Bartonella sp. (limited-term) and Mycoplasma sp. (lifelong), which commonly co-occur in wild rodents. We infected Bartonella- and Mycoplasma-free rodents with each species, and simultaneously with both, and quantified the infection dynamics and host responses. Bartonella benefited from the interaction; its infection load decreased more slowly in coinfected rodents than in rodents infected with Bartonella alone. There were no indications for bottom-up effects, but coinfected rodents experienced various changes, depending on the infection stage, in their body mass, stress levels and activity pattern, which may further affect bacterial replication and transmission. Interestingly, the infection dynamics and changes in the average coinfected rodent traits were more similar to the chronic effects of Mycoplasma infection, whereas coinfection uniquely impaired the host's physiological and behavioral stability. These results suggest that parasites with distinct life history strategies may interact, and their interaction may be asymmetric, non-additive, multifaceted and dynamic through time. Because multiple, sometimes contrasting, forms of interactions are simultaneously at play and their relative importance alternates throughout the course of infection, the overall outcome may change under different ecological conditions.

Haemoplasmas in wild rodents: Routes of transmission and infection dynamics.

The way that some parasites and pathogens persist in the hostile environment of their host for long periods remains to be resolved. Here, longitudinal field surveys were combined with laboratory experiments to investigate the routes of transmission and infection dynamics of such a pathogen-a wild rodent haemotropic bacterium, specifically a Mycoplasma haemomuris-like bacterium. Fleaborne transmission, direct rodent-to-rodent transmission and vertical transmission from fleas or rodents to their offspring were experimentally quantified, and indications were found that the main route of bacterial transmission is direct, although its rate of successful transmission is low (~20%). The bacterium's temporal dynamics was then compared in the field to that observed under a controlled infection experiment in field-infected and laboratory-infected rodents, and indications were found, under all conditions, that the bacterium reached its peak infection level after 25-45 days and then decreased to low bacterial loads, which persist for the rodent's lifetime. These findings suggest that the bacterium relies on persistency with low bacterial loads for long-term coexistence with its rodent host, having both conceptual and applied implications.

Untangling the knots: Co-infection and diversity of Bartonella from wild gerbils and their associated fleas.

Based on molecular data, previous studies have suggested a high overall diversity and co-infection rates of Bartonella bacteria in wild rodents and their fleas. However, partial genetic characterization of uncultured co-infecting bacteria limited sound conclusions concerning intra- and inter-specific diversity of the circulating Bartonella. To overcome this limitation, Bartonella infections of wild populations of two sympatric gerbil species and their fleas were explored by multiple isolations of Bartonella organisms. Accordingly, 448 pure Bartonella isolates, obtained from 20 rodent blood and 39 flea samples, were genetically characterized to the genotype and species levels. Results revealed a remarkable diversity and co-infection rates of Bartonella among these sympatric rodents and their associated fleas. Specifically, 38 genotypes, classified into four main Bartonella species, were identified. Co-infection was confirmed in 56% of the samples, which contained two to four Bartonella genotypes per sample, belonging to up to three different species. Recombination within and between these species was demonstrated, serving as a direct evidence of the frequent bacteria-bacteria interactions. Moreover, despite the noticeable interchange of common Bartonella genotypes between rodents and fleas, the co-occurrence of genotypes was not random and differences in the overall diversity, and the ecological and phylogenetic similarities of the infection compositions were significantly associated with the carrier type (rodent vs. flea) and the rodent species. Thus, comprehensive identification of the co-infecting organisms enabled the elucidation of ecological factors affecting the Bartonella distribution among reservoirs and vectors. This study may serve as a model for the investigation of other vector-borne organisms and their relationships with Bartonella.

Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience.

PURPOSE: Population screening for BRCA1/BRCA2. mutations is being considered for Ashkenazi Jews (AJ) because 2.5% carry recurrent deleterious mutations and effective cancer prevention exists. This study aimed to provide a qualitative focus on perspectives of individuals, particularly carriers, who were tested through a screening trial. In this trial, the pretest process included only written information. METHODS: Interviews were performed with 26 carriers and 10 noncarriers who participated in a BRCA population screening trial for AJ. RESULTS: Attitudes toward screening were generally positive. The main motivator for testing was knowledge of BRCA status to enable cancer risk reduction. Knowledge of carrier status, although challenging, was thus viewed as health-empowering. The screening paradigm was sensed as increasing awareness and as overcoming access, referral, and familial barriers. Streamlining the pretest process was positively perceived as offering gradual, stepwise knowledge commensurate with test results. Participants were concerned that health systems provide the necessary conceptual and infrastructural framework and that individual autonomy be maintained. CONCLUSIONS: BRCA screening in AJ is viewed favorably, even by carriers. Stepwise acquisition of knowledge based on test results was viewed as most relevant to the screening context. Screening program development should account for safeguarding autonomy and providing requisite post-test services.Genet Med advance online publication 01 December 2016.

Multiple effects of host-species diversity on coexisting host-specific and host-opportunistic microbes.

While host-species diversity often influences microbial prevalence, there may be multiple mechanisms causing such effects that may also depend on the foraging strategy of the microbes. We employed a natural gradient of rodent-species richness to examine competing hypotheses describing possible mechanisms mediating the relationship between host-species richness and the prevalence of the most dominant microbes, along with microbe specificity to the different rodent host species. We sampled blood from three gerbil species in plots differing in terms of the proportion of the different species and screened for the most dominant bacteria. Two dominant bacterial lineages were detected: host-specific bacteria and host-opportunistic bacteria. Using a model selection approach, we detected evidence for both direct and indirect effects of host-species richness on the prevalence of these bacteria. Infection probability of the host-specific lineage was lower in richer host communities, most likely due to increased frequency and density of the least suitable host species. In contrast, field observations suggest that the effect of host-species richness on infection probability of the opportunistic lineage was both direct and indirect, mostly mediated by changes in flea densities on the host and by the presence of the host-specific lineage. Our results thus suggest that host-species richness has multiple effects on microbial prevalence, depending on the degree of host-specificity of the microbe in question.

Humoral Immunity of Unvaccinated COVID-19 Recovered vs. Naïve BNT162b2 Vaccinated Individuals: A Prospective Longitudinal Study.

To study the differences in the immune response to SARS-CoV-2 infection compared to the response to vaccination, we characterized the humoral immune kinetics of these situations. In this prospective longitudinal study, we followed unvaccinated COVID-19-recovered individuals (n = 130) and naïve, two-dose BNT162b2-vaccinated individuals (n = 372) who were age- and BMI-matched for six months during the first pandemic year. Anti-RBD-IgG, neutralizing antibodies (NAbs), and avidity were assessed monthly. For recovered patients, data on symptoms and the severity of the disease were collected. Anti-RBD-IgG and NAbs titers at peak were higher after vaccination vs. after infection, but the decline was steeper (peak log IgG: 3.08 vs. 1.81, peak log NAbs: 5.93 vs. 5.04, slopes: -0.54 vs. -0.26). Peak anti-RBD-IgG and NAbs were higher in recovered individuals with BMI > 30 and in older individuals compared to individuals with BMI < 30, younger population. Of the recovered, 42 (36%) experienced long-COVID symptoms. Avidity was initially higher in vaccinated individuals compared with recovered individuals, though with time, it increased in recovered individuals but not among vaccinated individuals. Here, we show that while the initial antibody titers, neutralization, and avidity are lower in SARS-CoV-2-recovered individuals, they persist for a longer duration. These results suggest differential protection against COVID-19 in recovered-unvaccinated vs. naïve-vaccinated individuals.

Reduced Neutralization Efficacy against Omicron Variant after Third Boost of BNT162b2 Vaccine among Liver Transplant Recipients.

The immune responses of liver transplant (LT) recipients after the third boost of the BNT162b2mRNA vaccine improved. This study evaluates the durability of the immune response of LT recipients after the third boost, its predictors, and the impact of emerging variants. The receptor-binding domain IgG was determined at median times of 22 (first test) and 133 days (second test) after the administration of the third boost. IgG antibody titers > 21.4 BAU/mL were defined as a positive response. The neutralization efficacies of the vaccine against the wild-type, Omicron, and Delta variants were compared in the first test. The 59 LT recipients were of a median age of 61 years (range 25−82); 53.5% were male. Following administration of the third dose, the positive immune response decreased from 81.4% to 76.3% between the first and second tests, respectively, (p < 0.0001). The multivariate analysis identified CNI monotherapy (p = 0.02) and hemoglobin > 12 g/dL (p = 0.02) as independent predictors of a maintained positive immune response 133 days after the third dose. The geometric mean titers of Omicron neutralization were significantly lower than the wild-type and Delta virus (21, 137, 128, respectively; p < 0.0001). The immune response after the third BNT162b2mRNA vaccine dose decreased significantly in LT recipients. Further studies are required to evaluate the efficacy of the fourth vaccine dose and the durability of the immune response.

Real World Cost-Effectiveness Analysis of Population Screening for BRCA Variants among Ashkenazi Jews Compared with Family History-Based Strategies.

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier's relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (−3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.