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.

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.

COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022.

This work evaluated neutralising antibody titres against wild type (WT) SARS-CoV-2 and four Omicron variants (BA.1, BA.2, BA.4 and BA.5) in healthcare workers who had breakthrough BA.1 infection. Omicron breakthrough infection in individuals vaccinated three or four times before infection resulted in increased neutralising antibodies against the WT virus. The fourth vaccine dose did not further improve the neutralising efficiency over the third dose against all Omicron variants, especially BA.4 and BA.5. An Omicron-specific vaccine may be indicated.

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.

Patterns and Predictors of Staphylococcus aureus Carriage during the First Year of Life: a Longitudinal Study.

We sought here to investigate the patterns of Staphylococcus aureus carriage in the first year of life, its determinants, and the dynamics of transmission between mothers and infants. A prospective longitudinal cohort study of S. aureus carriage among mothers and their infants was performed, including monthly screenings from pregnancy/birth through the first year of the infant's life. Medical and lifestyle data were collected. Infant S. aureus carriage was detected from rectal and nasal swabs, and maternal carriage was detected from nasal and vaginal swabs. Multivariate analysis and a nonlinear mixed model (NLMIXED) were used to determine the predictors of carriage and S. aureus persistence. Of the 671 women recruited, 130 women carried S. aureus at recruitment (19.3%); they and their 132 infants were included in the study. A total of 93% of the infants acquired S. aureus sometime during the first year of life; 64% of these infants acquired the maternal strain, mostly (66%) during the first month of life. We observed that 70 women (52.50%) and 17 infants (14%) carried S. aureus persistently. Early acquisition of S. aureus carriage was associated with longer duration of initial carriage and was the most significant predictor of S. aureus persistence, while day care center attendance was negatively associated with persistent carriage. Methicillin-resistant S. aureus was carried by two infants for only 1 month each and not by any of the mothers. Early acquisition of S. aureus, mostly from the mother, is thus an important determinant of carriage persistence in infancy.

Genomic epidemiology of meticillin-resistant Staphylococcus aureus ST22 widespread in communities of the Gaza Strip, 2009.

BackgroundRemarkably high carriage prevalence of a community-associated meticillin-resistant Staphylococcus aureus (MRSA) strain of sequence type (ST) 22 in the Gaza strip was reported in 2012. This strain is linked to the pandemic hospital-associated EMRSA-15. The origin and evolutionary history of ST22 in Gaza communities and the genomic elements contributing to its widespread predominance are unknown. Methods: We generated high-quality draft genomes of 61 ST22 isolates from Gaza communities and, along with 175 ST22 genomes from global sources, reconstructed the ST22 phylogeny and examined genotypes unique to the Gaza isolates. Results: The Gaza isolates do not exhibit a close relationship with hospital-associated ST22 isolates, but rather with a basal population from which EMRSA-15 emerged. There were two separate resistance acquisitions by the same MSSA lineage, followed by diversification of other genetic determinants. Nearly all isolates in the two distinct clades, one characterised by staphylococcal cassette chromosome mec (SCCmec) IVa and the other by SCCmec V and MSSA isolates, contain the toxic shock syndrome toxin-1 gene. Discussion: The genomic diversity of Gaza ST22 isolates is not consistent with recent emergence in the region. The results indicate that two divergent Gaza clones evolved separately from susceptible isolates. Researchers should not assume that isolates identified as ST22 in the community are examples of EMRSA-15 that have escaped their healthcare roots. Future surveillance of MRSA is essential to the understanding of ST22 evolutionary dynamics and to aid efforts to slow the further spread of this lineage.

Sink-traps are a major source for carbapenemase-producing Enterobacteriaceae transmission.

OBJECTIVE: We studied the extent of carbapenemase-producing Enterobacteriaceae (CPE) sink contamination and transmission to patients in a nonoutbreak setting. METHODS: During 2017-2019, 592 patient-room sinks were sampled in 34 departments. Patient weekly rectal swab CPE surveillance was universally performed. Repeated sink sampling was conducted in 9 departments. Isolates from patients and sinks were characterized using pulsed-field gel electrophoresis (PFGE), and pairs of high resemblance were sequenced by Oxford Nanopore and Illumina. Hybrid assembly was used to fully assemble plasmids, which are shared between paired isolates. RESULTS: In total, 144 (24%) of 592 CPE-contaminated sinks were detected in 25 of 34 departments. Repeated sampling (n = 7,123) revealed that 52%-100% were contaminated at least once during the sampling period. Persistent contamination for >1 year by a dominant strain was common. During the study period, 318 patients acquired CPE. The most common species were Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. In 127 (40%) patients, a contaminated sink was the suspected source of CPE acquisition. For 20 cases with an identical sink-patient strain, temporal relation suggested sink-to-patient transmission. Hybrid assembly of specific sink-patient isolates revealed that shared plasmids were structurally identical, and SNP differences between shared pairs, along with signatures for potential recombination events, suggests recent sharing of the plasmids. CONCLUSIONS: CPE-contaminated sinks are an important source of transmission to patients. Although traditionally person-to-person transmission has been considered the main route of CPE transmission, these data suggest a change in paradigm that may influence strategies of preventing CPE dissemination.

The impact of PCV7/13 on the distribution of carried pneumococcal serotypes and on pilus prevalence; 14 years of repeated cross-sectional surveillance.

BACKGROUND: S. pneumoniae carriage by children is a major source of pneumococcal transmission, and the initial step prior to infection. Pilus type 1, reported in ~30% of pneumococcal strains in the pre-vaccine era, contributes to pneumococcal colonization and virulence. In this study, we report the impact of the pneumococcal conjugate vaccine (PCV), PCV7/PCV13 sequential implementation on serotype distribution, and on the prevalence of piliated strains among carried pneumococci during the pre- and post-vaccine eras. METHODS: During 2002-2016, 12 repeated cross-sectional surveillances of nasopharyngeal S. pneumoniae carriage were conducted among 8,473 children <5.5 years old visiting primary care physicians in Central Israel. Seven biannual surveillances in the pre-PCV period, 2 surveillances after PCV7 was licensed but before implementation in the National Immunization Plan, and 3 additional surveillances in the post-PCV period. S. pneumoniae serotype distribution and prevalence of piliated strains were assessed. RESULTS: Carriage of S. pneumoniae was relatively stable (45.4%). The prevalence of serotypes included in PCV13 was 65.7%, in the pre-vaccine period and the pilus was present in 26.4% of isolates. The distribution of serotypes and the pilus prevalence in the pre-PCV period was relatively stable except for a decrease in prevalence of piliated 19F, observed following the first study year. Following PCV7/PCV13 implementation, vaccine type 13 (VT13) strains were nearly eliminated to 3.3% by 2016. Piliated strains, which were primarily of VT13 serotypes, initially followed a similar trend and were nearly eliminated by 2014 (1.7%). Yet, two years later, pilus prevalence re-emerged among non-VT strains to 12.8% of all pneumococci. CONCLUSIONS: Following PCV implementation, a dramatic and rapid decrease in VT strains prevalence was observed with a concomitant increase in non-VT strains. Piliated strains were nearly eliminated, yet re-emerged 7 years following PCV7/PCV13 implementation in various non-VT strains. This suggests that the pilus confers an advantage in colonization.

Determinants of Staphylococcus aureus carriage in the developing infant nasal microbiome.

BACKGROUND: Staphylococcus aureus is a leading cause of healthcare- and community-associated infections and can be difficult to treat due to antimicrobial resistance. About 30% of individuals carry S. aureus asymptomatically in their nares, a risk factor for later infection, and interactions with other species in the nasal microbiome likely modulate its carriage. It is thus important to identify ecological or functional genetic elements within the maternal or infant nasal microbiomes that influence S. aureus acquisition and retention in early life. RESULTS: We recruited 36 mother-infant pairs and profiled a subset of monthly longitudinal nasal samples from the first year after birth using shotgun metagenomic sequencing. The infant nasal microbiome is highly variable, particularly within the first 2 months. It is weakly influenced by maternal nasal microbiome composition, but primarily shaped by developmental and external factors, such as daycare. Infants display distinctive patterns of S. aureus carriage, positively associated with Acinetobacter species, Streptococcus parasanguinis, Streptococcus salivarius, and Veillonella species and inversely associated with maternal Dolosigranulum pigrum. Furthermore, we identify a gene family, likely acting as a taxonomic marker for an unclassified species, that is significantly anti-correlated with S. aureus in infants and mothers. In gene content-based strain profiling, infant S. aureus strains are more similar to maternal strains. CONCLUSIONS: This improved understanding of S. aureus colonization is an important first step toward the development of novel, ecological therapies for controlling S. aureus carriage.

Sink traps as the source of transmission of OXA-48-producing Serratia marcescens in an intensive care unit.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) outbreaks are mostly attributed to patient-to-patient transmission via healthcare workers. OBJECTIVE: We describe successful containment of a prolonged OXA-48-producing S. marcescens outbreak after recognizing the sink traps as the source of transmission. METHODS: The Sheba Medical Center intensive care unit (ICU), contains 16 single-bed, semi-closed rooms. Active CPE surveillance includes twice-weekly rectal screening of all patients. A case was defined as a patient detected with OXA-48 CPE >72 hours after admission. A root-cause analysis was used to investigate the outbreak. All samples were inoculated on chrom-agar CRE, and carbapenemase genes were detected using commercial molecular Xpert-Carba-R. Environmental and patient S. marcescens isolates were characterized using PFGE. RESULTS: From January 2016 to May 2017, 32 OXA-48 CPE cases were detected, and 81% of these were S. marcescens. A single clone was the cause of all but the first 2 cases. The common factor in all cases was the use of relatively large amounts of tap water. The outbreak clone was detected in 2 sink outlets and 16 sink traps. In addition to routine strict infection control measures, measures taken to contain the outbreak included (1) various sink decontamination efforts, which eliminated the bacteria from the sink drains only temporarily and (2) educational intervention that engaged the ICU team and lead to high adherence to 'sink-contamination prevention guidelines.' No additional cases were detected for 12 months. CONCLUSIONS: Despite persistence of the outbreak clones in the environmental reservoir for 1 year, the outbreak was rapidly and successfully contained. Addressing sink traps as hidden reservoirs played a major role in the intervention.

Comparison of early effects of pneumococcal conjugate vaccines: PCV7, PCV10 and PCV13 on Streptococcus pneumoniae nasopharyngeal carriage in a population based study; The Palestinian-Israeli Collaborative Research (PICR).

BACKGROUND: Pneumococcal conjugate vaccines (PCVs), PCV10 and PCV13, are currently used in different countries. We have previously reported the effectiveness of PCV7, following its introduction in Israel and before PCVs were introduced in Palestine. Here, we extended the study and compared the initial impact of PCV10 to that of PCV7/13. METHODS: Four cross-sectional surveys of S. pneumoniae carriage among children <5y through 2009-2014 were preformed among two proximate populations, living under two distinct health authorities, with different vaccination policies. In East-Jerusalem (EJ), PCV7 was implemented in 2009 and replaced by PCV13 in late 2010, while in Palestine (PA), PCV10 was implemented in 2011. RESULTS: A total of 1267 and 2414 children from EJ and PA were screened. In 2014, S. pneumoniae was detected in 30.7% and 28.6% of the children in EJ and PA respectively Implementation of both PCV7 (in EJ) and PCV10 (in PA) did not affect overall S. pneumoniae carriage, but resulted in a significant decrease in the prevalence of vaccine-type strains. In the pre-vaccine era, VT7/VT13 strains consisted 47.0%/62.0% and 41.2%/54.8% of pneumococci in EJ and PA, respectively. A 48.6% and 53.9% decrease in VT7 strains was observed within 3 years of PCV7 implementation in EJ (p = 0.001) and PCV10 in PA (p<0.0001), respectively. These vaccination policies also resulted in ~50% reduction in VT13-added serotypes especially 6A (from 11.0% to 0.0% (EJ) and 9.5% to 4.9% (PA)). Three years after PCV13 implementation in EJ, an additional 67% decrease in VT13 strains was observed, yet an increase in serotype 3 was observed (0.0% to 3.4%, p = 0.056). While the prevalence of VT13 strains decreased significantly during the study period, the overall carriage rate didn't change significantly due to replacement with non-VT13 strains which comprised 89.8% and 70.7% of all pneumococci, in EJ and in PA respectively in the last study year. CONCLUSIONS: Within the first three years following PCV implementation, we observed similar reductions in carriage of VT10 and VT13 strains with either vaccination policies, with no effect on overall carriage. Further follow-up is needed to compare the long-term effects.

Clinical evaluation of early acquisition of Staphylococcus aureus carriage by newborns.

BACKGROUND: Little is known about neonatal Staphylococcus aureus carriage. Sites and clinical outcomes of S. aureus colonization during the first month of life were evaluated in this study. METHODS: A cohort of 279 infants born at term to 277 mothers was included. Maternal S. aureus colonization status was examined before labor. Newborns were screened for nasal, auricular, umbilical, and rectal colonization, one to three times within 100h after birth, and infants of carrier mothers were re-screened at 1 month. Medical data were recorded from the medical charts at discharge and at the 1-month follow-up interview. RESULTS: Overall 43 out of 279 (15.4%) infants acquired S. aureus within the first days of life. The only two predictors of S. aureus carriage in the postnatal period were maternal S. aureus carriage (odds ratio 7.905, 95% confidence interval 3.182-19.638) and maternal antibiotic treatment during labor (odds ratio 0.121, 95% confidence interval 0.016-0.949). Among colonized children, the nose (56%) and rectum (40%) were more frequently colonized, while ear (26%) and umbilicus (16%) colonization were less common. Co-colonization at two sites was rare (4%), but always predicted carriage at 1 month of age. Maternal and neonatal characteristics, including neonatal outcomes, were similar between S. aureus carrier and non-carrier infants during the first month of life. CONCLUSIONS: Maternal carriage is the major predictor of neonatal S. aureus carriage. The nose and rectum are the main sites of neonatal carriage. S. aureus carriage was not associated with neonatal complications throughout the first month of life. The long-term significance of early S. aureus carriage is yet to be determined.

Vaccine escape of piliated Streptococcus pneumoniae strains.

INTRODUCTION: Type1-pilus proteins were suggested as targets of future protein-based vaccines. Here we studied the effect of pneumococcal-conjugate vaccine (PCV7) implementation on the prevalence of piliated strains in a unique study setting which controls for typical confounders; the Palestinian-Israeli Collaborative Research (PICR). METHODS: Annual cross-sectional surveys of pneumococcal carriage were performed during 2009-2011 among two closely related population that live under different health policies (a) Palestinian-Authority (PA) (n=1773), where PCV7 was not yet introduced (b) East-Jerusalem (EJ) (n=983) where PCV7 was rapidly implemented. Clinical data were collected, pneumococci identified and characterized and the presence of Type1-pilus genes was determined by rrgC PCR. RESULTS: Following PCV7 implementation in EJ, overall carriage prevalence did not change (∼30%), but VT7 strains decreased from 61.5% to 33.8%. While prevalence of non-piliated-VT7 isolates decreased from 37% to 10%, p<0.001, the prevalence of piliated-VT7 strains persisted ∼25%. Additionally, piliated non-VT13 strains emerged (1-15%, p<0.001). These changes were not observed in PA. These dynamics were independent of the bacteria's resistance pattern. CONCLUSIONS: A differential effect of PCV7 was observed with a relative resistance of piliated strains to the vaccine. This suggests that Type1-pilus confers an intrinsic advantage for colonization and may be an attractive vaccine target.

Measuring the effects of pneumococcal conjugate vaccine (PCV7) on Streptococcus pneumoniae carriage and antibiotic resistance: the Palestinian-Israeli Collaborative Research (PICR).

BACKGROUND: The Palestinian-Israeli Collaborative Research (PICR) cross-conflict setting provided a unique opportunity to study overall and indirect effects of pneumococcal conjugate vaccine (PCV7), in two closely related Palestinian populations governed by two distinct health authorities with distinct vaccination policies. Here, PCV7 effects on pneumococcal carriage, serotype distribution and antibiotic resistance are reported. METHODS: Annual cross-sectional surveys of pneumococcal carriage were performed during 2009-2011 among Palestinian children (≤5 years) (a) under Palestinian-Authority (PA) health policy (Ramallah, Nablus and Bethlehem), where PCV7 was unlicensed (b) under Israeli health policy (East-Jerusalem (EJ)) where PCV7 was rapidly implemented from July 2009. Clinical data were collected, pneumococci identified and characterized for antibiotic susceptibilities and serotype. Analyses included multivariate logistic models with an interaction term for PCV7-effect. RESULTS: Altogether, 2755 children from PA (n=1772) and EJ (n=983) were enrolled, of which ~30% were pneumococcal carriers. While overall carriage was not affected by vaccination policy, carriage of vaccine-type (VT7) strains decreased from 52% to 22% (p<0.001) in EJ, where PCV was implemented, but not in PA. This was accompanied by an increase in non-VT13 strains from 34% to 65% (p<0.001) in EJ, but not in PA. Furthermore, within two years post-PCV7 introduction, proportion of multi-drug resistant strains, which was initially 23% in both populations, decreased significantly in EJ, to 10%, while simultaneously it increased in PA to 33% (p<0.001). Similar trends were observed for resistance to most antibiotic groups. The proportion of resistant isolates among non-VT13 strains did not change during the study period. CONCLUSIONS: The unique study design distinguishes secular and seasonal effects from true vaccine effects. While PCV7 did not affect overall pneumococcal carriage rate, VT7 strains, many of which were antibiotic resistant decreased and were replaced by non-VT13 strains, which were mostly not antibiotic resistant, resulting in a net decrease in antibiotic resistance.