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In Slovenia, primary acellular pertussis vaccines (ACVs) containing pertactin (PRN) were mostly used during 1999-2016; ACVs without PRN were introduced in 2017. Among 123 Bordetella pertussis strains collected during 2002-2020, a total of 48 were PRN-deficient; 44 were collected after 2017. Changes to ACVs could increase PRN-deficient B. pertussis and infections. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Setting Population or Sample Methods Main Outcome Measures Results Conclusions Adverse birth outcomes and the maternal severity of influenza in pregnancy are well documented but information on pertussis is limited.Population‐based linkage data were collected during 2001–2016.New South Wales, Australia.A total of 1 453 037 singleton births.Cox regression was used to estimate the associations between pertussis or influenza during pregnancy and birth outcomes with adjustment of covariates.Adverse birth outcomes (preterm birth and low birth weight).Among 1 453 037 singleton births over 16 years, we identified pertussis in 925 (49; 5.3% hospitalised) and influenza in 2850 (1092; 38.3% hospitalised) women during pregnancy. Cases of pertussis were similarly distributed by trimester (32% 3rd) whereas 46% of influenza cases were in the 3rd trimester. Younger age, previous birth, and being overseas‐born were associated with both pertussis and influenza, whereas identifying as Aboriginal or Torres Strait Islander, hypertension or diabetes before and during pregnancy, and a number of other factors were only associated with influenza. Both pertussis and influenza in pregnancy were associated with increased risk of preterm birth (pertussis: aHR = 1.30, 95% CI 1.01–1.68; influenza: aHR = 1.56, 95% CI 1.36–1.79) and these increased risks were greater when infections in the period within 2 weeks of birth were considered (pertussis: aHR = 2.36, 95% CI 1.26–4.41; influenza: aHR = 2.29, 95% CI 1.78–2.96).Maternal pertussis and influenza infections close to the time of birth were associated with adverse birth outcomes. These findings highlight the benefits of vaccination during pregnancy. [ABSTRACT FROM AUTHOR]

Pertussis is a vaccine-preventable respiratory disease caused by the Gram negative coccobacillus Bordetella pertussis. The licensed acellular pertussis (aP) vaccines protect against disease but do not prevent bacterial colonization and transmission. Here, we developed and tested an intranasal vaccine composed of aP antigens combined with T-vant, a novel adjuvant derived from bacterial outer membrane vesicles, that elicits both mucosal and systemic immune responses. We hypothesized that immunization of mice with aP-T-vant would enhance mucosal immunity and eliminate B. pertussis in the respiratory tract. In contrast to mice immunized intramuscularly with the licensed aP vaccine, intranasal immunization with aP-T-vant eliminated bacteria in both the lung and nasopharynx. Protection was associated with IFN-gamma and IL-17-producing, non-circulating CD4 + T cells in the lung and nasopharynx, and sterilizing immunity in the nasopharynx was dependent on IL-17. Novel mucosal adjuvants, such as T-vant, warrant further investigation to enhance the efficacy of next generation pertussis vaccines. [ABSTRACT FROM AUTHOR]

Background: Pertussis is a highly contagious, vaccine-preventable acute respiratory infection caused by Bordetella pertussis (B. Pertussis) and affects all age groups. Since 1947, the Global Expanded Program on Immunization (EPI) was executed, and its incidence has been effectively curtailed. The reasons for the resurgence are multifactorial including the waning of vaccine acquired immunity, the difference in vaccination strategies, the adaptation of B. Pertussis strains, and an increase in disease awareness due to the strengthening of diagnostic sensitivity and surveillance sensitivity. Notably, Hewlett and Edwards proposed that the shift in pertussis transmission patterns plays an important role in pertussis resurgence. Diphtheria is an acute infectious disease of upper respiratory tract caused by toxigenic strains of Corynebacterium Diphtheriae (CD) and Corynebacterium other than diphtheriae (COD). The organism is locally invasive and causes exotoxin - mediated illness and can lead to complications like stridor, respiratory obstruction, myocarditis, nerve palsy, renal insufficiency and death in severe cases. The objective of the present study is to isolate and identify the etiological agents in clinically suspected cases of Diphtheria and Pertussis. Materials & Methods: This Prospective study has been conducted in the department of Microbiology from Feb 2022 to Aug 2024. Samples with high clinical suspicion were received and processed. Two Throat swabs were collected in patients with clinical suspicion of Diphtheria. They were inoculated on Blood agar, Potassium Tellurite agar, Tinsdale agar. Gram staining and Albert staining were done. Molecular testing also performed for C. diphtheriae. Two nasopharyngeal swabs were collected in patients with clinical suspicion of Pertussis. They were inoculated on Bordet Gengou medium, Charcoal Agar with Cephalexin and Blood Agar and Mac Conkey agar. Gram Staining was performed and Biochemical testing was carried out. Molecular testing was carried out for B. Pertussis and B. parapertussis. Results: Out of 53 samples with clinical suspicion of Diphtheriae, 6 were positive for Corynebacterium diphtheria by culture. Molecular testing was also done for testing of rpo B gene and Tox A gene. 6 samples came to be positive for C. diphtheria rpo B gene where as one was positive for tox gene production. Out of 20 cases with strong suspicion of Pertussis, culture was positive for Bordetella pertussis in 2 samples. Molecular testing came out to be positive for one sample. Testing for the antibodies by ELISA two patients were serologically positive for Pertussis. Both Culture and molecular testing was positive in one sample. Both culture and serology was positive in one sample. Only serology was positive in one sample. Conclusion: A constant surveillance is needed for vaccine preventable diseases to predict the outbreak or resurgence of cases. [ABSTRACT FROM AUTHOR]

Background: Hesitancy about vaccination during pregnancy posed challenges to SARS-CoV-2 vaccination efforts. We aimed to examine rates of SARS-CoV-2 vaccination among Ontario residents who gave birth in early 2022, and to compare rates of SARS-CoV-2 vaccine uptake with rates of tetanus, diphtheria, and pertussis (Tdap) and influenza vaccination during pregnancy in 2019, 2021, and 2022. Methods: We conducted a population-based retrospective cohort study to describe vaccination rates among pregnant and comparable nonpregnant populations in Ontario using linked administrative data. Provincially insured females who had a live, in-hospital birth from Jan. 1 to Mar. 31 in 2019, 2021, or 2022 were our primary cohort. Using log-binomial regression, we tested associations between SARS-CoV-2 (2022) and Tdap and influenza (2019, 2021, 2022) vaccination status, with birth group and covariates. We compared SARS-CoV-2 vaccination status with the status of a matched cohort of nonpregnant females and conducted subgroup analyses by age and prenatal clinician type. Results: Among birthing people, 78.7% received their first SARS-CoV-2 vaccine dose and 74.2% received a second dose. The rate was significantly higher among nonpregnant comparators (dose 1: relative risk [RR] 0.94, 95% confidence interval [CI] 0.93–0.94; dose 2: RR 0.91, 95% CI 0.90–0.91). However, the rate of SARS-CoV-2 vaccination uptake among birthing people was higher than uptake of Tdap or influenza vaccination. Tetanus, diphtheria, and pertussis vaccination increased over time from 22.2% in 2019 to 32.6% in 2022, and influenza vaccination rose to 35.3% in 2021 but returned to prepandemic levels in 2022 (27.7%). Vaccination rates were lower among pregnant people who were young, multiparous, or residents of rural or economically deprived areas for all 3 vaccines. Interpretation: Rates of SARS-CoV-2 vaccination were lower among pregnant people than among nonpregnant comparators but were higher than rates of routinely recommended Tdap and influenza vaccinations. Pandemic urgency may have overcome a great deal of hesitancy about vaccinating against SARS-CoV-2 during pregnancy in 2022, but uptake of routinely recommended vaccines in pregnancy remains a challenge. Trial registration: Clinicaltrials.gov, no. NCT05663762. [ABSTRACT FROM AUTHOR]

Bordetella pertussis infection is a highly contagious respiratory disease that can cause complications such as pneumonia and death. A total of 62,646 cases of pertussis worldwide were reported by WHO in 2022. This study aimed to obtain the pertussis seroprevalence and sociodemographic data in children aged 1–14 years and its association factors in the community based on Riskesdas 2013 and 2018. Bivariate and multivariate analysis was carried out on data from 12,753 children aged 1–14 years collected from Riskesdas 2013 and 2018 in Indonesia. Pertussis serology data was obtained based on the results of the ELISA examination which was categorized as seropositive if anti-pertussis toxin IgG ≥ 100 IU/mL or anti-pertussis IgG > 11 NTU. Pertussis seropositive indicated recent pertussis infection if no pertussis vaccine was received within the last twelve months. Pertussis seroprevalence was found at 9.8% and 33.4% in Riskesdas 2013 and 2018 respectively. While 10.1% of children aged 5–14 years were found pertussis seropositive by excluding the possible effect of vaccination in the last twelve months in Riskesdas 2013. The most important associated factor in seropositive pertussis at ages 1–4 years and 5–14 years was a history of pneumonia in the last month (OR = 2.709, 95%CI: 2.592–2.831 in Riskesdas 2013 and OR = 2.421, 95%CI: 2.299–2.550 in Riskesdas 2018). In the adjusted analysis for respondents' characteristics, low maternal education was the predictive factor that most influenced pertussis seropositivity, especially in the 2013 Riskesdas (APOR = 2.983, 95%CI: 2.670–3.333). In conclusion, the results of this study showed that the seroprevalence of pertussis was high, especially in children aged 5–14 years, so that pertussis vaccine booster administration could be considered. Because the most influencing factor towards pertussis seropositive was low maternal education, the groups of children with low-educated mothers should be targets for strengthening complete vaccination coverage and disease control. [ABSTRACT FROM AUTHOR]

The objective was to determine if antigen-specific tissue-resident memory T (TRM) cells persist in respiratory tissues of adults immunized as children with whole-cell pertussis (wP) or acellular pertussis (aP) vaccines. Mononuclear cells from tonsil or nasal tissue cells were cultured with Bordetella pertussis antigens and TRM cells quantified by flow cytometry. Adults immunized with wP vaccines as children had significantly more interleukin 17A (IL-17A) and interferon-γ (IFN-γ)–producing TRM cells that respond to B. pertussis antigens in respiratory tissues when compared with aP-primed donors. Our findings demonstrate that wP vaccines induce CD4 TRM cells that can persist in respiratory tissues for decades. [ABSTRACT FROM AUTHOR]

Background: Healthcare professionals (HCPs) play a significant role in the decision-making process of pregnant women on maternal vaccinations. Whereas a high proportion of HCPs discuss maternal vaccinations with pregnant women, confidence in discussing maternal vaccinations is lacking and HCPs experience inadequate training to discuss maternal vaccinations with pregnant women. Furthermore, different practical barriers might influence the consultation process, such as lack of time. More studies on the barriers, as well as facilitators, to discussing maternal vaccinations is needed and will help us to better understand and support HCPs in discussing maternal vaccinations. Methods: This qualitative study involved semi-structured interviews with fourteen HCPs working as midwives or gynaecologists in the Netherlands. An integrated theoretical approach was used to inform data collection and analysis. Thematic analysis was conducted using inductive and deductive approaches. This study followed the COnsolidated criteria for REporting Qualitative research (COREQ) guidelines. Results: The thematic analysis of the data pointed to the following five themes of HCP counselling: the consultation process, attitude, perceived norm, perceived control and improvement ideas. Most HCPs follow a similar approach in maternal pertussis vaccination consultations, beginning by assessing clients' understanding, providing basic information, and addressing questions. However, consultation timing and prioritization vary among HCPs. Challenges in consultations include client requests for clear advice, with HCPs trained to remain neutral, emphasizing client autonomy in decision-making. Most HCPs acknowledge the importance of their consultations in informing pregnant women about maternal pertussis vaccination. Conclusions: This study offers a confirmation of the awareness of the pivotal role of HCPs in informing pregnant women about the maternal pertussis vaccination. HCPs stress the importance of neutral counselling, enabling pregnant women to make well-informed decisions independently. Because of upcoming vaccine hesitancy nowadays, HCPs must be equipped with the knowledge and confidence to navigate difficult conversations. Continuous education and training might help to increase HCPs' confidence in handling difficult consultations. Additionally, making the information materials for pregnant women available in multiple languages and incorporating more visuals to enhance comprehension could support HCPs in reaching a broader group of pregnant women. [ABSTRACT FROM AUTHOR]

Introduction: A resurgence of pertussis has been reported in numerous countries. This study aimed to determine the incidence, clinical characteristics, and outcome of pertussis among infants in Sarawak, Malaysia. Methodology: We conducted a descriptive retrospective study of infants aged < 12 months with laboratory-confirmed pertussis admitted to Bintulu Hospital in Sarawak, Malaysian Borneo, from 2015 until 2021. Pertussis was confirmed in all patients using a polymerase chain reaction of nasopharyngeal aspirates. Results: Of 588 infants who had a nasopharyngeal aspirate, 108 (18%) had laboratory-confirmed pertussis. The average annual incidence was 482 per 100,000 infants aged < 12 months between 2015 and 2019, with a marked decline in 2020 and 2021. Eighty-two (76%) were < 3 months of age. Seventy-eight (72%) were unvaccinated for pertussis, including 75 (96%) who were too young to receive the first dose. A third of the cases had atypical presentations. Severe disease characterized by hypoxemia, pulmonary hypertension, recurrent apnea, encephalopathy, or cardiovascular dysfunction occurred in 32%. Forty-eight percent required humidified high-flow nasal cannula oxygen therapy and 22% required invasive ventilation. Twenty-four percent overall needed intensive care. One (1%) infant had a fatal outcome. Nearly all cases of severe disease or those that required invasive ventilation or intensive care had received = 1 dose of pertussis vaccination. Conclusions: A high incidence of pertussis with a high rate of severe disease was observed in Sarawak, Malaysia, predominantly among infants too young to be vaccinated. Additional vaccination strategies such as maternal vaccination or cocooning should be considered. [ABSTRACT FROM AUTHOR]

Maternal vaccines during pregnancy offer crucial protection against infections for both the pregnant person and their newborn. Vaccines against influenza, pertussis, coronavirus disease 2019, and respiratory syncytial virus are routinely recommended by the Centers for Disease Control and Prevention to safeguard pregnant women and their infants from potentially severe complications. Administering these vaccines during pregnancy helps transfer protective antibodies from the mother to the baby, enhancing immunity during the vulnerable early months of life. Extensive research supports the safety and efficacy of maternal vaccines, with numerous studies demonstrating their protective benefits for both pregnant people and newborns. [ABSTRACT FROM AUTHOR]

In the last twelve months, a significant global increase in pertussis cases has been observed, particularly among infants under three months of age. This age group is at the highest risk for severe disease, hospitalization, and death. Maternal immunization with the Tdap vaccine during pregnancy has been recommended to protect newborns by transferring maternal antibodies transplacentally. This review examines the current epidemiology of pertussis, the importance of preventing it in young children, and the effectiveness of maternal immunization. Despite the proven benefits of maternal vaccination, which has been found effective in pertussis prevention in up to 90% of cases, coverage remains suboptimal in many countries. Factors contributing to low vaccination rates include vaccine hesitancy due to low trust in health authority assessments, safety concerns, practical barriers to vaccine access, and the impact of the COVID-19 pandemic, which disrupted routine vaccination services. The recent increase in pertussis cases may also be influenced by the natural cyclic nature of the disease, increased Bordetella pertussis (Bp) activity in older children and adults, and the genetic divergence of circulating Bp strains from vaccine antigens. Given the high efficacy of maternal vaccination in preventing pertussis in infants, increasing coverage rates is crucial. Efforts to improve vaccine uptake should address barriers to access and vaccine hesitancy, ensuring consistent immune protection for the youngest and most vulnerable populations. Enhanced maternal vaccination could significantly reduce the incidence of whooping cough in infants, decreasing related hospitalizations and deaths. [ABSTRACT FROM AUTHOR]

Pertussis vaccination is recommended during pregnancy to protect the baby. Pertussis vaccination was initially free to pregnant people through general practice and hospitals in New Zealand, but uptake was suboptimal. In one district funding of maternal pertussis vaccination was widened to community pharmacies in 2016. Eighteen months later promotion to pharmacies, midwives and pregnant people took place. In 2020 and 2021, COVID-19 lockdowns occurred. Aim. To explore the effects of promotion and COVID-19 lockdowns on uptake of funded maternal pertussis vaccination in pharmacy, and awareness, use and opinions of promotional elements. Methods. Five years of pharmacy claims data were analysed and 12 pharmacists, 18 people eligible/recently eligible for maternal pertussis vaccination and 11 midwives were interviewed. Results. Provision of maternal pertussis vaccination increased during and after promotion. Qualitative data showed that pharmacists valued phone calls with information about maternal pertussis vaccination and recommendations for increasing uptake. Prompted by these calls, some pharmacists contacted midwives to inform them of funded maternal pertussis vaccination in the pharmacy (which midwives appreciated) and recommended pertussis vaccination to pregnant clients. Pharmacy staff reportedly were motivated to recommend this vaccination by being informed about it and having posters displayed in the pharmacy. Pregnant people valued healthcare professionals' conversations about maternal pertussis vaccination, but appeared to be uninfluenced by posters and promotional social media posts about this vaccination. During COVID-19, maternal pertussis uptake in pharmacies increased 31% March to May 2020 (before and during the first COVID-19 lockdown) versus the same time the previous year, then declined. Conclusion. Promotion appeared to have a sustained effect on uptake of maternal pertussis vaccination in pharmacies. Pregnant people were most influenced by discussions with healthcare professionals. Pharmacists and pharmacy staff increased proactivity with maternal vaccinations after promotion to them. Promotion may need to be repeated over time. [ABSTRACT FROM AUTHOR]

Lot release testing of diphtheria, tetanus and acellular pertussis vaccines traditionally relied on in vivo protection models involving challenge of laboratory animals with toxins. Meanwhile, many labs have switched to serological testing of these vaccines, which is often performed in separate in vivo assays, even if all components were formulated into one vaccine product. Here we describe the results of simultaneous serological potency determination of diphtheria (D), tetanus (T) and acellular pertussis (aP) antigens obtained following immunization of guinea pigs with multicomponent pediatric and booster vaccines from different manufacturers. The 4th World Health Organization (WHO) International Standard (IS) for diphtheria toxoid (No. 07/216) and the 4th WHO IS for tetanus toxoid (No. 08/218) were used as reference preparations. For aP, a pediatric vaccine batch containing the antigens pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae proteins type 2/3 was established as internal control. Quantification of IgG against D, T and aP antigens in guinea pig sera was performed using a hexaplex electrochemiluminescence immunoassay. We further provide proof-of-concept using experimental vaccine samples lacking or containing reduced amounts of diphtheria toxoid in the presence of full amounts of tetanus and pertussis antigens and alum adjuvant. Importantly, the assay confirmed dose-response relationships for all antigens tested and was able to detect diphtheria out-of-specification batches. The results confirmed the suitability of the protocol for combined serology batch release testing of DTaP combination vaccines as first measure towards implementation of full in vitro testing of DTaP vaccines. This report summarizes the data and the protocol used for validation prior to implementation of this method in routine batch release testing of DTaP vaccines, which led to replacement of in vivo challenge experiments in our laboratory following the 3 R (replace, reduce, refine) principle. [ABSTRACT FROM AUTHOR]

Acellular pertussis vaccines (aPVs) have been developed as an alternative to whole-cell pertussis vaccines (wPVs) because of their similar efficacy but reduced reactogenicity. The aPV contains 3 or more immunogenic components of Bordetella pertussis. We aimed to evaluate the immunogenicity and protective potency of an aPV vaccine produced in our laboratory consisting of pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) in mice. The aPV components were produced and purified from the supernatant and pellet of the bacterial culture. Two doses of the formulated vaccine, in parallel with two commercial vaccines, were administered intraperitoneally to mice at 3-week intervals. Antibody titers against aPV antigens were measured by enzyme-linked immunosorbent assay (ELISA) after primary and booster vaccinations. To assess the protective efficacy, an intranasal challenge with a live pathogenic B pertussis strain was conducted 2 weeks after the booster vaccination, and bacterial counts (colony-forming units [CFUs]) in the lungs were determined 2 hours and 10 days after the challenge. The results demonstrated a significant increase in antibody titers against all pertussis antigens in the serum of the vaccinated groups compared with the negative control group, following both the primary and booster doses. No significant differences were observed between our formulation and the commercial vaccines. Furthermore, the CFU results after the challenge showed complete eradication of infection 10 days after the challenge in all immunized groups, in contrast to the control group. Our aPV formulation, the first aPV candidate developed in Iran, exhibits immunogenicity and protective efficacy comparable to those of commercial vaccines. Further investigation of human subjects is warranted. [ABSTRACT FROM AUTHOR]

Background: Pertussis is a highly contagious respiratory illness mainly caused by Bordetella pertussis (BP). Bordetella parapertussis (BPP) can induce symptoms compatible with pertussis, but has been underdiagnosed and underreported. The current pertussis vaccines offer low protection against BPP. Herein, we aim to reveal the epidemiology and genomic evolution of BPP in Shanghai, China. Methods: Children diagnosed with BPP infection from January 2017 to December 2022 in Shanghai, China were enrolled. We performed antimicrobial susceptibility testing (AST), multiple locus variable-number tandem repeat analysis (MLVA), and whole genome sequencing (WGS) analysis. A total of 260 international BPP genomes were chosen for comparison to investigate the genomic diversity and phylogenetic characteristics of Chinese strains within a global context. Results: Sixty patients were diagnosed with BPP infection by culture, with the positive ratio of 3.5‰ (60/17337) for BPP in nasopharyngeal swap samples. The average age of patients was 4.5 ± 0.3 years. BPPs contained four MLVA types including MT6 (65.0%), MT4 (26.7%), untype-1 (6.7%) and MT5 (1.7%), and none of strains showed resistance to macrolides. All strains carried virulence genotype of ptxP37/ptxA13/ptxB3/ptxC3/ptxD3/ptxE3/fim2-2/fim3-10. MT4 and MT5 strains carried prn54, whereas MT6 and untype-1 BPPs expressed prn101. We identified two outbreaks after 2020 caused by MT4 and MT6 strains, each corresponding to distinct WGS-based phylogenetic lineages. The MT4-lineage is estimated to have originated around 1991 and has since spread globally, being introduced to China between 2005 and 2010. In contrast, the MT6-lineage was exclusively identified in China and is inferred to have originated around 2002. Conclusion: We revealed the genomic diversity of BPPs circulating in Shanghai, China, and reported the outbreaks of MT6 and MT4 BPPs after 2020. This is the first report on the emergence and regional outbreak of MT6 BPPs in the world, indicating that continuous surveillance on BPPs are thus required. [ABSTRACT FROM AUTHOR]

Continued circulation of the whooping cough pathogen, even in countries with high vaccine coverage, can be related to persistence of Bordetella pertussis biofilms in the respiratory tract. The films differ from planktonic cells by increased resistance to the host immune system and antibacterial drugs. The available acellular pertussis vaccines (aPV) containing antigens isolated from planktonic cultures of B. pertussis protect from severe forms of whooping cough, but do not effectively influence circulation of virulent strains in the subclinical forms of the disease and asymptomatic carriage. It is promising to create new generation aPV based on antigens isolated from biofilm cultures of B. pertussis capable of more effectively controlling the entire infectious cycle of whooping cough, including colonization, persistence, and transmission of the pathogen. From antigenic complexes isolated from the culture medium of biofilm and planktonic cultures of the strain B. pertussis No. 317 (serotype 1.2.3), experimental aPV were made: aPV-B and aPV-P, respectively. In intracerebral infection of mice with a virulent strain of B. pertussis, aPV-B demonstrated 2.5-fold higher protective activity than aPV-P and also more effectively reduced colonization of the lungs by B. pertussis cells in mice after intranasal infection with a virulent strain. Both vaccine preparations were safe and did not cause death in mice after administration of histamine. [ABSTRACT FROM AUTHOR]

Background In 2020, the Council of State and Territorial Epidemiologists (CSTE) pertussis case definition was modified; the main change was classifying polymerase chain reaction (PCR)-positive cases as confirmed, regardless of cough duration. Pertussis data reported through Enhanced Pertussis Surveillance (EPS) in 7 sites and the National Notifiable Diseases Surveillance System (NNDSS) were used to evaluate the impact of the new case definition. Methods We compared the number of EPS cases with cough onset in 2020 to the number that would have been reported based on the prior (2014) CSTE case definition. To assess the impact of the change nationally, the proportion of EPS cases newly reportable under the 2020 CSTE case definition was applied to 2020 NNDSS data to estimate how many additional cases were captured nationally. Results Among 442 confirmed and probable cases reported to EPS states in 2020, 42 (9.5%) were newly reportable according to the 2020 case definition. Applying this proportion to the 6124 confirmed and probable cases reported nationally in 2020, we estimated that the new definition added 582 cases. Had the case definition not changed, reported cases in 2020 would have decreased by 70% from 2019; the observed decrease was 67%. Conclusions Despite a substantial decrease in reported pertussis cases in the setting of coronavirus disease 2019 (COVID-19), our data show that the 2020 pertussis case definition change resulted in additional case reporting compared with the previous case definition, providing greater opportunities for public health interventions such as prophylaxis of close contacts. [ABSTRACT FROM AUTHOR]

Background: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods and findings: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Conclusions Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registration: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371998&isReview=true. Just one registry (as above). Gladymar Pérez Chacón and colleagues report the safety and immunogenicity of a mixed whole-cell and acellular pertussis vaccine in Australian infants in stage 1 of the two-stage OPTIMUM trial. Author summary: Why was this study done?: Evidence-based strategies to lower the risk of food allergies developing in young children are limited. A previous observational study suggested that food allergies appear to be less common among Australian-born children vaccinated with a first dose of whole-cell whooping cough (wP) vaccine before 4 months old versus those receiving a first dose of acellular whooping cough (aP) vaccine at the same age. Why did the researchers do and find?: In the first stage of a 2-stage, double-blind, noninferiority trial, Australian-born infants were randomised to receive a first dose of wP versus aP at approximately 6 weeks old; in both study groups, aP vaccine is given at 4 and 6 months old. Stage (phase) one examined the immunogenicity, reactogenicity, and IgE-mediated immune responses of the mixed vaccine schedule (wP/aP/aP) versus the standard aP-only vaccination strategy (aP/aP/aP) in a cohort of 150 infants; stage two is ongoing and was designed to ascertain the development of food allergy by 12 months old (primary outcome) in a cohort of up to 3,000 infants. At 7 months old, the mixed schedule was noninferior to the standard aP-only strategy with respect to pertussis toxin IgG responses; at the same age, we observed no difference across the study groups in IgE responses to hen's egg and tetanus toxoid antigens. The mixed schedule was more reactogenic but well accepted by parents. What do these findings mean?: These findings support the acceptable immunogenicity and reactogenicity of the mixed schedule and are relevant for countries in which wP and aP vaccines are licensed and readily available. While the reported IgE responses are not conclusive, further studies of CD4+ T cell polarisation in response to pertussis antigens, along with primary outcome data will provide a comprehensive picture of the atopic immunophenotypic responses across the study groups. Additional evidence is required to understand the population-level acceptability of the mixed vaccination strategy. [ABSTRACT FROM AUTHOR]

Acellular multivalent vaccines for pertussis (DTaP and Tdap) prevent symptomatic disease and infant mortality, but immunity to Bordetella pertussis infection wanes significantly over time resulting in cyclic epidemics of pertussis. The messenger RNA (mRNA) vaccine platform provides an opportunity to address complex bacterial infections with an adaptable approach providing Th1-biased responses. In this study, immunogenicity and challenge models were used to evaluate the mRNA platform with multivalent vaccine formulations targeting both B. pertussis antigens and diphtheria and tetanus toxoids. Immunization with mRNA formulations were immunogenetic, induced antigen specific antibodies, as well as Th1 T cell responses. Upon challenge with either historical or contemporary B. pertussis strains, 6 and 10 valent mRNA DTP vaccine provided protection equal to that of 1/20th human doses of either DTaP or whole cell pertussis vaccines. mRNA DTP immunized mice were also protected from pertussis toxin challenge as measured by prevention of lymphocytosis and leukocytosis. Collectively these pre-clinical mouse studies illustrate the potential of the mRNA platform for multivalent bacterial pathogen vaccines. [ABSTRACT FROM AUTHOR]

Bordetella pertussis, which causes a respiratory disease known as pertussis ("whooping cough") remains an important global challenge, with the incidence in pertussis cases increasing in recent years. Newborns and infants are at increased risk for severe morbidity and mortality from this bacterium. Vaccination in pregnancy has become an important strategy to both passively transfer immunity as well as prevent infection in pregnant persons, who are a major source of newborn infection, thus attempting to decrease the impact of this serious disease. It is considered safe for the pregnant person, the developing fetus, and the infant, and during the first 3 months of life it has been shown to be highly effective in preventing pertussis. There are a variety of strategies, recommendations, and adherence rates associated with pertussis vaccination in pregnancy around the world. We summarize the 2021 Global Pertussis Initiative Annual Meeting that reviewed the current global status of pertussis vaccination in pregnancy and remaining medical and scientific questions, with a focus on vaccination challenges and strategies for obstetric and gynecologic healthcare providers. Synopsis: Newborns/infants remain at high risk for severe morbidity/mortality from pertussis infection. Vaccination in pregnancy has become a key strategy to reduce this serious and potentially fatal disease. Herein, we focus on vaccination challenges and strategies for obstetric and gynecologic health care providers. [ABSTRACT FROM AUTHOR]

Pertactin (PRN), a non-fimbrial outer membrane protein of Bordetella pertussis, is the limiting component of the acellular pertussis vaccine because of its low concentration. This study aimed to develop a large-scale urea-based process for PRN extraction from B. pertussis. Cell pellet processing conditions, including freezing and thawing, were found to substantially affect PRN yield. A single cycle of rapid freezing of the cell pellet at − 30 °C with slow thawing at 5 ± 3 °C resulted in up to fivefold higher PRN yield than condition without freezing and thawing. The search for urea treatment conditions was also conducted, and 5 M urea treatment for 2 h was the optimal condition. The developed urea-based process was applied to 50 L culture scale, and residual impurities were removed by sequential anion exchange, hydrophobic interaction and gel filtration chromatography and resulted in PRN with a purity of over 95% at a yield of 33.2%. From 50 L culture broth, the final yield of PRN per cell pellet was 0.23 mg/g (wet weight). Thus, a large-scale production process for high-quality PRN from B. pertussis was developed based on urea extraction process. The results may serve as a reference for production of other membrane proteins. [ABSTRACT FROM AUTHOR]

The article focuses on whooping cough (pertussis), detailing its history, transmission dynamics, diagnostic methods, complications, and the evolution of vaccination strategies. It highlights the resurgence of pertussis outbreaks, particularly affecting infants, and emphasizes the critical role of vaccination in controlling its spread, despite challenges such as vaccine hesitancy and waning immunity.

• Coverage of measles and pertussis childhood vaccines in Norway vary by parental immigrant background. • East-European background was often associated with relatively low and recently declining coverage of both vaccines. • Somali background was associated with relatively low coverage of measles vaccine, but not of pertussis vaccine. • Mother's length of residency was positively associated with coverage among children of East-European or Vietnamese background. The Norwegian Childhood Immunization Program maintains a high national coverage of 95–97% in the most recent years. Whether there are subgroups with lower uptake is less studied. This study examines pertussis and measles vaccination coverage among six immigrant groups in Norway. These vaccines are normally administered as part of different combination vaccines and their coverage rate indicate the national vaccination coverage against a range of additional infections. Data from the Norwegian National Population Register were linked at individual level with vaccination data from the Norwegian Immunisation Registry. The final sample consisted of 53,052 children born during 2000–2018 in Norway to parents who were born in Iraq, Lithuania, Pakistan, Poland, Somalia, or Vietnam. Vaccination coverage was measured at 2-years of age. Multivariate linear regression was utilized to estimate the relationship between vaccinations status, year of birth, gender, mother's length of residency in Norway, and area of residence. At two years of age, the majority of the children were vaccinated. Coverage among the groups varied at, above, and below the national average for the two vaccines. For most of the years examined, children born by parents from Lithuania, Poland, and Somalia had lower coverage for the measles vaccine (range 81–84% in 2020) than the national level (97% in 2020). Children born by parents from the Eastern-European countries also had lower coverage than the national level for the pertussis vaccine (range 87–89% in 2020). This study illustrates how subgroups with lower vaccination coverage may exists within a well-established vaccination program with high national coverages. Differences in coverage were found for both vaccines, but the differences were more pronounced for the measles vaccine. The high vaccination coverage in Norway provides indirect protection through herd immunity for unvaccinated individuals, however, the lower vaccination coverage in some immigrant groups is a concern. [ABSTRACT FROM AUTHOR]

Maternal pertussis vaccination during the third trimester of pregnancy was implemented in 2015 in Spain, reaching a national coverage of 84% in 2019. In this ecological study, we investigated whether there was a change in the disease severity for pertussis in infants upon introduction of prenatal pertussis vaccination. We performed a time-trend analysis of infant pertussis hospitalizations during 2005–2019 in Spain using national register data. Annual hospitalization rates per 100,000 population and the mean length of hospitalization were calculated for infants < 3 months of age (target group benefiting from the prenatal vaccination) and a reference group aged 3–11 months. We compared overall rates and annual percent changes of the above variables in both groups for the time period before (2005–2014) and after vaccination introduction (2015–2019), using segmented Poisson regression. During the pre-vaccination period, infants aged 0–2 months had a 5-times higher rate of pertussis hospitalization and spent on average 50 % longer in hospital than the reference group. After the maternal vaccination introduction, the hospitalization rate decreased more rapidly in infants aged 0–2 months than in infants aged 3–11 months: annual reduction of 34 % (95 % CI: 31–38) versus 26 % (95 % CI: 21–31) in the hospitalization rate and 13 % (95 % CI: 11–15) versus 6 % (95 % CI: 2–9) in the mean hospital stay, respectively. In 2019, the mean hospital stay for pertussis was about 4.5 days in both groups. Maternal pertussis vaccination in Spain led to a reduction in disease severity in the target group as compared to older infants, highlighting the need for increased efforts on educating healthcare professionals on the importance of maternal vaccinations. [ABSTRACT FROM AUTHOR]

The IgG response following infant diphtheria-tetanus-acellular pertussis (DTaP) immunization is influenced by the formulation of the infant and/or the adult vaccine (Tdap) given during pregnancy. DTaP vaccines containing either 3 (DTaP3) or 5 (DTaP5) pertussis antigens are commonly used. By conducting a secondary analysis of a large randomized controlled trial, we compared IgG levels against pertussis vaccine antigens in children of Td- and Tdap5-vaccinated mothers, after stratifying by infant vaccine formulation. After immunization with a primary series of DTaP5, but not DTaP3, IgG GMCs against pertussis antigens were significantly lower in infants of Tdap-immunized mothers compared with infants of Td-vaccinated mothers (pertussis toxin: GMC = 52.3[Tdap5] vs 83.5[Td], p < 0.001). Before and after the DTaP booster dose, IgG GMCs were similar in infants of Tdap- and Td-immunized mothers specifically when infants received the DTaP3 vaccine. The combination of the TdaP5 vaccine for mothers and the DTaP3 vaccine for children could attenuate Tdap-associated immunomodulation. [ABSTRACT FROM AUTHOR]

• PERTINENT, a four-year hospital-based European network for pertussis in infants aged 0–11 months. • Sole network for independent, multi-country pertussis vaccine effectiveness studies in Europe. • One vaccine dose in infants aged 2–5 months would halve the risk of being hospitalised for pertussis. • Dose-dependent increase of vaccine effectiveness against hospitalisation due to pertussis. • At least one dose of acellular vaccine in infants continues to offer good protection for pertussis. Monitoring effectiveness of pertussis vaccines is necessary to adapt vaccination strategies. PERTINENT, Pertussis in Infants European Network, is an active sentinel surveillance system implemented in 35 hospitals across six EU/EEA countries. We aim to measure pertussis vaccines effectiveness (VE) by dose against hospitalisation in infants aged <1 year. From December 2015 to December 2019, participating hospitals recruited all infants with pertussis-like symptoms. Cases were vaccine-eligible infants testing positive for Bordetella pertussis by PCR or culture; controls were those testing negative to all Bordetella spp. For each vaccine dose, we defined an infant as vaccinated if she/he received the corresponding dose >14 days before symptoms. Unvaccinated were those who did not receive any dose. We calculated (one-stage model) pooled VE as 100*(1-odds ratio of vaccination) adjusted for country, onset date (in 3-month categories) and age-group (when sample allowed it). Of 1,393 infants eligible for vaccination, we included 259 cases and 746 controls. Median age was 16 weeks for cases and 19 weeks for controls (p < 0.001). Median birth weight and gestational age were 3,235 g and week 39 for cases, 3,113 g and week 39 for controls. Among cases, 119 (46 %) were vaccinated: 74 with one dose, 37 two doses, 8 three doses. Among controls, 469 (63 %) were vaccinated: 233 with one dose, 206 two doses, 30 three doses. Adjusted VE after at least one dose was 59 % (95 %CI: 36–73). Adjusted VE was 48 % (95 %CI: 5–71) for dose one (416 eligible infants) and 76 % (95 %CI: 43–90) for dose two (258 eligible infants). Only 42 infants were eligible for the third dose. Our results suggest moderate one-dose and two-dose VE in infants. Larger sample size would allow more precise estimates for dose one, two and three. [ABSTRACT FROM AUTHOR]

Purpose: Pertussis bacteria have many pathogenic and virulent antigens and severe adverse reactions have occurred when using inactivated whole-cell pertussis vaccines. Therefore, inactivated acellular pertussis (aP) vaccines and genetically detoxified recombinant pertussis (rP) vaccines are being developed. The aim of this study was to assess the safety profile of a novel rP vaccine under development in comparison to commercial diphtheria-tetanusacellular pertussis (DTaP) vaccines. Materials and Methods: The two positive control DTaP vaccines (two- and tri-components aP vaccines) and two experimental recombinant DTaP (rDTaP) vaccine (two- and tri-components aP vaccines adsorbed to either aluminum hydroxide or purified oat beta-glucan) were used. Temperature histamine sensitization test (HIST), indirect Chinese hamster ovary (CHO) cell cluster assay, mouse-weight-gain (MWG) test, leukocytosis promoting (LP) test, and intramuscular inflammatory cytokine assay of the injection site performed for safety assessments. Results: HIST results showed absence of residual pertussis toxin (PTx) in both control and experimental DTaP vaccine groups, whereas in groups immunized with tri-components vaccines, the experimental tri-components rDTaP absorbed to alum showed an ultra-small amount of 0.0066 IU/mL. CHO cell clustering was observed from 4 IU/mL in all groups. LP tests showed that neutrophils and lymphocytes were in the normal range in all groups immunized with the two components vaccine. However, in the tri-components control DTaP vaccine group, as well as two- and tri-components rDTaP with beta-glucan group, a higher monocyte count was observed 3 days after vaccination, although less than 2 times the normal range. In the MWG test, both groups showed changes less than 20% in body temperature and body weight before the after the final immunizations. Inflammatory cytokines within the muscle at the injection site on day 3 after intramuscular injection revealed no significant response in all groups. Conclusion: There were no findings associated with residual PTx, and no significant differences in both local and systemic adverse reactions in the novel rDTaP vaccine compared to existing available DTaP vaccines. The results suggest that the novel rDTaP vaccine is safe. [ABSTRACT FROM AUTHOR]

• Proactive recommendations by obstetricians play a key role in the implementation of vaccination in pregnancy but is still insufficient in our setting. • Future efforts should aim to explore possible hurdles that impede recommendations by obstetricians for vaccination in pregnancy. • Local campaigns do not seem effective enough to increase vaccination in pregnancy, therefore national campaigns with new strategies are desirable. Pertussis and influenza are endemic infections and associated with relevant morbidity and mortality in newborns and young infants. The Swiss Federal Office of Public Health has recommended influenza vaccination since 2011 and pertussis vaccination in pregnancy (ViP) since 2013 and expanded to repetition in each pregnancy since 2017. ViP is safe and effective in preventing severe diseases, but implementation is a challenge. We hypothesized that the proportion of women receiving ViP is persistently low despite existing national recommendations. Our primary objective was to compare the proportion of pertussis and influenza vaccine recommendations for and its acceptance by pregnant women before and after an information campaign tailored to obstetricians. Secondly, we aimed to identify reasons for missing or declining ViP. We conducted a prospective, single-center, single-arm implementation study in the maternity ward at the University Women's Hospital Basel. We performed standardized interviews with women hospitalized for postpartum care before (October to December 2019, Phase 1, n = 262) and after an information campaign (October to December 2020, Phase 2, n = 233) and compared categorical variables using chi-squared or Fisher's exact test and continuous variables using Whitney Mann U test. We found no significant differences in the proportion of recommendation for pertussis ViP (80 % vs. 84 %, p = 0.25) and implementation (76 % vs. 78 %, p = 0.63) between Phase 1 and 2. Main reasons for missing or declining vaccinations were lack of recommendation (62.8 %) and safety concerns regarding the unborn child (17.7 %). In contrast, the proportion of recommendation for influenza ViP (45 % vs. 63 %, p < 0.001) and implementation (29 % vs. 43 %, p < 0.001) increased significantly. Proactive recommendations by obstetricians play a key role in the implementation of ViP but is still insufficient in our setting. We believe that future efforts should aim to explore possible hurdles that impede recommendations by obstetricians for ViP. The focus should be on the needs and experiences of obstetricians in private practice, but also other health care professionals involved in care of pregnant women. Local campaigns do not seem effective enough, therefore national campaigns with new strategies are desirable. [ABSTRACT FROM AUTHOR]

• Cost-effectiveness analysis of booster fifth-dose DTaP vaccination. • Reflection of herd immunity from vaccinated adolescents to unvaccinated infants. • DTaP booster is expected to reduce pertussis cases in adolescents. • DTaP booster to adolescents would be cost-effective when the morbidity is high. In Japan, the introduction of a fifth diphtheria–tetanus–acellular pertussis (DTaP) vaccination has been considered, and adolescents aged 11–12 years old who are currently receiving the diphtheria–tetanus (DT) vaccine are one candidate group. We analyze the cost-effectiveness of replacing the DT vaccine with the DTaP vaccine for 11-year-old adolescents and investigate the indirect effect of vaccinated adolescents on unvaccinated infant siblings. We undertake two analyses using high- and low-morbidity pertussis cases, and based on the results, present suggestions for pertussis prevention in the post-COVID-19 pandemic era. We used the number of pertussis cases in 2019 as the high-morbidity case and the average number of cases in 2020–2021 as the low-morbidity case, and evaluated the incremental cost-effectiveness ratio (ICER) of the DTaP strategy to the DT strategy based on quality-adjusted life years (QALYs). The economic model contained adolescent and infant sub-models. The indirect effect for infants was considered as the probability of unvaccinated infants avoiding pertussis infection from their vaccinated siblings. The ICER from the payers' perspective was Japanese yen (JPY) 4,254,515 per QALY gained in the high-morbidity case and JPY 62,546,776 per QALY gained in the low-morbidity case. The sensitivity analysis showed that the utility of pertussis had the greatest impact on the ICER, with a 60.58% and 0% probability that the ICER was less than JPY 5 million per QALY gained in the high-morbidity case and low-morbidity case, respectively. The cost-effectiveness of replacing the DT vaccine with the DTaP vaccine is affected by the level of pertussis morbidity, with the ICER becoming more favorable in the high-morbidity case. The indirect effect has little impact on the ICER. Thus, policy-makers should continue to monitor the pertussis epidemic in the post-COVID-19 era, and determine the need to introduce a booster based on perceived trends. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effectiveness of maternal pertussis vaccination for preventing pertussis infections in Aboriginal and Torres Strait Islander infants under seven months of age. Study design: Retrospective cohort study; analysis of linked administrative health data. Setting, participants: Mother–infant cohort (Links2HealthierBubs) including all pregnant women who gave birth to live infants (gestational age ≥ 20 weeks, birthweight ≥ 400 g) in the Northern Territory, Queensland, and Western Australia during 1 January 2012 – 31 December 2017. Main outcome measures: Proportions of women vaccinated against pertussis during pregnancy, rates of pertussis infections among infants under seven months of age, and estimated effectiveness of maternal vaccination for protecting infants against pertussis infection, each by Indigenous status. Results: Of the 19 892 Aboriginal and Torres Strait Islander women who gave birth to live infants during 2012–2017, 7398 (37.2%) received pertussis vaccine doses during their pregnancy, as had 137 034 of 259 526 non‐Indigenous women (52.8%; Indigenous v non‐Indigenous: adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.62–0.70). The annual incidence of notified pertussis infections in non‐Indigenous infants declined from 16.8 (95% CI, 9.9–29) in 2012 to 1.4 (95% CI, 0.3–8.0) cases per 10 000 births in 2017; among Aboriginal and Torres Strait Islander infants, it declined from 47.6 (95% CI, 16.2–139) to 38.6 (95% CI, 10.6–140) cases per 10 000 births. The effectiveness of maternal vaccination for protecting non‐Indigenous infants under seven months of age against pertussis infection during 2014–17 was 68.2% (95% CI, 51.8–79.0%); protection of Aboriginal and Torres Strait Islander infants was not statistically significant (36.1%; 95% CI, –41.3% to 71.1%). Conclusions: During 2015–17, maternal pertussis vaccination did not protect Aboriginal and Torres Strait Islander infants in the NT, Queensland, and WA against infection. Increasing the pertussis vaccination rate among pregnant Aboriginal and Torres Strait Islander women requires culturally appropriate, innovative strategies co‐designed in partnership with Indigenous organisations and communities. [ABSTRACT FROM AUTHOR]

Pertussis is an important cause of mortality and morbidity in infancy. It is recommended that close contacts of the baby be vaccinated with Tdap, and this practice is called the cocoon strategy. This study aimed to investigate the applicability of the cocoon strategy and to determine the factors affecting the process. Mothers of babies who were hospitalized in the neonatal intensive care unit were included in the study. In the first stage, a face-to-face questionnaire was given to the mothers to measure their level of knowledge about whooping cough and its vaccine. In the second stage, written and verbal information about the cocoon strategy was given, and then vaccination intentions for Tdap were learned. In the third stage, all mothers were contacted 3 weeks after and asked whether they had received a Tdap vaccination and why. Of these mothers, 68% could not answer any questions about pertussis disease and vaccines correctly. After the information, 35% (n = 78) of the mothers stated that they were considering getting vaccinated, while only 2% (n = 5) of the mothers were able to get the Tdap vaccine. The most important reasons for not getting vaccinated were a lack of time (24%) and the cost of vaccination (23%). It is predicted that Tdap vaccination rates may increase if the cost of vaccine, availability of vaccine, and the access of mothers to the vaccine application are facilitated. [ABSTRACT FROM AUTHOR]

Background: Pertussis, or whooping cough, is a global public health concern. Pertussis vaccines have demonstrated good protection against Bordetella pertussis infections, but their effectiveness against Bordetella parapertussis remains debated due to conflicting study outcomes. Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of pertussis vaccines in protecting children against B. parapertussis infection. A comprehensive search of PubMed, Web of Science, and Scopus databases was conducted, and randomized controlled trials (RCTs) and observational studies that met inclusion criteria were included in the analysis. Results: The meta-analysis, involving 46,533 participants, revealed no significant protective effect of pertussis vaccination against B. parapertussis infection (risk ratio: 1.10, 95% confidence interval: 0.83 to 1.44). Subgroup analyses by vaccine type and study design revealed no significant protection. The dearth of recent data and a limited pool of eligible studies, particularly RCTs, underscore a critical gap that warrants future research in the domain. Conclusions: These findings offer crucial insights into the lack of effectiveness of pertussis vaccines against B. parapertussis. Given the rising incidence of cases and outbreaks, coupled with the lack of cross-protection by the existing vaccines, there is an urgent need to develop vaccines that include specific antigens to protect against B. parapertussis. [ABSTRACT FROM AUTHOR]

Background: In the Americas, deaths by diseases avoidable with vaccines are a significant contributor to child mortality. An essential means of reducing this is through broad vaccine coverage. The COVID-19 pandemic has posed a potential disruption to vaccine coverage due to its effects on the healthcare system. Objectives: this study aims to evaluate the impact of the COVID-19 pandemic on DTP3 vaccination coverage in the Americas, investigating trends from 2012 to 2022 to identify significant changes, regional disparities, and the overall effect of the pandemic on progress towards global immunization targets. Methods: This study used the coverage data for the third dose of the diphtheria, tetanus, and pertussis vaccine (DTP3) pulled from UNICEF databases spanning 2012 to 2022. We conducted a Joinpoint regression to identify points of significant trend changes. The annual percentage change (APC) and 95% confidence intervals (95% CIs) were calculated for America and its regions. We also used segmented regression analysis. Using the Chi-square test, we compared DTP3 vaccination coverage for each country between 2019 and 2022. Results: Overall, America saw a decrease in vaccine coverage during this period, with an APC of −1.4 (95% CI −1.8; −1.0). This trend varied across regions. In North America, the decrease was negligible (−0.1% APC). South America showed the steepest decrease, with an APC of −2.5%. Central America also declined, with an APC of −1.3%. Our findings suggest a concerning trend of declining DTP-vaccination rates in the Americas, exacerbated in certain regions, in the wake of the COVID-19 pandemic. The absolute decrease in vaccine coverage in the Americas was −4% between 2019 and 2022, with the most important drop being in Central America (−7%). However, six countries reported increased vaccination rates post-COVID-19, led by Brazil, with a 7% increase. Conversely, twenty-two countries registered a decline in DTP3 vaccine coverage, with the average decrease being −7.37%. This decline poses an important challenge to achieving the WHO's target of 90% coverage for the third dose of DTP by 2030, as evidenced by the reduction in the number of countries meeting this target from 2019 to 2022. Conclusions: The COVID-19 pandemic has impacted vaccine coverage in America, leading to a decrease, especially across Central America. [ABSTRACT FROM AUTHOR]

A decade ago, we described a new approach to discover next generation adjuvants, identifying small-molecule immune potentiators (SMIPs) as Toll-like receptor (TLR)7 agonists. We also optimally formulated these drugs through adsorption to aluminum salts (alum), allowing them to be evaluated with a range of established and early-stage vaccines. Early proof-of-concept studies showed that a TLR7 agonist (TLR7a)-based SMIP, when adsorbed to alum, could perform as an effective adjuvant for a variety of different antigens, in both small and large animals. Studies in rodents demonstrated that the adjuvant enhanced immunogenicity of a recombinant protein-based vaccine against Staphylococcus aureus, and also showed potential to improve existing vaccines against pertussis or meningococcal infection. Extensive evaluations showed that the adjuvant was effective in non-human primates (NHPs), exploiting a mechanism of action that was consistent across the different animal models. The adjuvant formulation (named AS37) has now been advanced into clinical evaluation. A systems biology-based evaluation of the phase I clinical data with a meningococcal C conjugate vaccine showed that the AS37-adjuvanted formulation had an acceptable safety profile, was potent, and activated the expected immune pathways in humans, which was consistent with observations from the NHP studies. In the intervening decade, several alternative TLR7 agonists have also emerged and advanced into clinical development, such as the alum adsorbed TLR7/8 SMIP present in a widely distributed COVID-19 vaccine. This review summarizes the research and early development of the new adjuvant AS37, with an emphasis on the steps taken to allow its progression into clinical evaluations. [ABSTRACT FROM AUTHOR]

Background Pertussis is a contagious respiratory disease. Maternal tetanus–diphtheria–acellular pertussis vaccination during pregnancy has been recommended by the United States Centres for Disease Control (US CDC) Advisory Committee on Immunization Practices (ACIP) for unvaccinated pregnant women since October 2011 to prevent infection among infants; in 2012, ACIP extended this recommendation to every pregnancy, regardless of previous vaccination status. The population-level effect of these recommendations on infant pertussis is unknown. This study aimed to examine the impact of the 2011/2012 ACIP pertussis recommendation on pertussis incidence and mortality among US infants. Methods We used monthly data on pertussis deaths among infants aged <1 year between January 2005 and December 2017 in the CDC Death Data and yearly infant pertussis incidence data from the CDC National Notifiable Disease Surveillance System to perform an interrupted time series analysis, accounting for the passage of the Affordable Care Act. Results This study included 156 months of data. A potential decline in trend in infant pertussis incidence was noted during the post-recommendations period. No appreciable differences in trend were found in population-level infant pertussis mortality after the guideline changes in both adjusted and unadjusted models. Results were similar for all mortality sensitivity analyses. Conclusions The 2011/2012 ACIP maternal pertussis vaccination recommendations were not associated with a population-level change in the trend in mortality, but were potentially associated with a decrease in incidence in the USA between 2005 and 2017. [ABSTRACT FROM AUTHOR]

Background: Pertussis is a highly contagious and dangerous respiratory disease that threatens children's health in many countries, including Vietnam, despite vaccine coverage. From 2015 to 2018, Vietnam experienced an increasing number of pertussis patients. Therefore, this study aimed to investigate the trend and examine the seasonal variations of pertussis in North Vietnam. Methods: Data were collected from medical records of all under-5-year-old inpatients admitted to the National Children's Hospital in Hanoi, Vietnam (VNCH) 2015–2018. A descriptive analysis was performed to describe the distribution of incident cases by year and season. Linear multivariable regression was conducted to investigate the association between the incidence of cases and seasonality adjusted by age and vaccination status. Results: We identified 1063 laboratory-confirmed patients during 2015–2018, including 247 (23.2%) severe patients. The number of pertussis patients admitted to VNCH per 1000 hospitalizations was 3.2 in 2015, compared to 1.9, 3.1, and 2.1 in 2016, 2017, and 2018, respectively. Outbreaks occurred biennially; however, there was no significant difference in the number of severe patients over this period. Most cases occurred in the hot season (509 patients, or nearly half of the study population). With the adjustment of the vaccination rate and average age, the risk of pertussis-associated hospitalization in the mild season and the hot season was 21% (95% CI [0.12; 0.3]) and 15% (95% CI [0.05; 0.25]) higher than that in the warm season, respectively. The rate of hospitalizations was high in the mild season (28.9%) and the warm season (30.8%), nearly twice as much as that in the hot season; nevertheless, the death rate was only striking high in the mild season, about 5–6 times as much as those in the other seasons. Conclusion: The pertussis incidence in Northern Vietnam varied between seasons, peaking in the hot season (April-July). However, severe patients and deaths increased in the mild season (December-March). Interventions, for example, communication activities on pertussis and vaccination, are of immense importance in lowering the prevalence of pertussis. In addition, early diagnoses and early warnings performed by health professionals should be encouraged. [ABSTRACT FROM AUTHOR]

Vaccinations are the most effective and economically beneficial form of preventing dangerous infectious diseases. Healthcare professionals should strive for the highest possible immunisation rate in the population, especially among patients from risk groups, which include pregnant women. The vaccination coverage among pregnant Polish women is still unsatisfactory. A consensus on vaccination of pregnant women has recently been achieved by the greatest scientific authorities: global organisations and scientific societies recommend all pregnant women to be vaccinated against pertussis, influenza and COVID-19. Vaccination during pregnancy leads to the production of post-vaccination antibodies that migrate transplacentally to the foetus, providing protection to infants in their first months of life. The inactivated influenza vaccine is safe and effective when given at any stage of pregnancy. Vaccination against pertussis should take place between week 27 and 36 of pregnancy. The COVID-19 vaccine can be administered simultaneously with other vaccines or with a 14-day interval. The American Congress of Obstetricians and Gynecologists (ACOG) recommends vaccination of pregnant women with mRNA COVID-19 vaccines at any stage of pregnancy. As a general rule, pregnant women should not be vaccinated with live, attenuated viruses or bacterial vaccines. Vaccines contraindicated for pregnant individuals, such as the vaccine against measles, mumps, rubella and varicella, as well as HPV, can be administered after delivery and during the breastfeeding period. Vaccination of pregnant women against rabies or tetanus is necessary for post-exposure prophylaxis. [ABSTRACT FROM AUTHOR]

Few data exist on asymptomatic carriage of Bordetella species among populations receiving acellular pertussis vaccine. We conducted a cross-sectional study among acellular-vaccinated children presenting to an emergency department (ED). Bordetella pertussis carriage prevalence was <1% in this population, a lower prevalence than that found in recent studies among whole-cell pertussis-vaccinated participants. [ABSTRACT FROM AUTHOR]

Since the 2000s, sporadic outbreaks of whooping cough have been reported in advanced countries, where the acellular pertussis vaccination rate is relatively high, and in developing countries. Small-scale whooping cough has also continued in many countries, due in part to the waning of immune protection after childhood vaccination, necessitating the development of an improved pertussis vaccine and vaccination program. Currently, two different production platforms are being actively pursued in Korea; one is based on the aP (acellular pertussis) vaccine purified from B. pertussis containing pertussis toxoid (PT), filamentous hemagglutin (FHA) and pertactin (PRN), and the other is based on the recombinant aP (raP), containing genetically detoxified pertussis toxin ADP-ribosyltransferase subunit 1 (PtxS1), FHA, and PRN domain, expressed and purified from recombinant E. coli. aP components were further combined with diphtheria and tetanus vaccine components as a prototype DTaP vaccine by GC Pharma (GC DTaP vaccine). We evaluated and compared the immunogenicity and the protective efficacy of aP and raP vaccines in an experimental murine challenge model: humoral immunity in serum, IgA secretion in nasal lavage, bacterial clearance after challenge, PTx (pertussis toxin) CHO cell neutralization titer, cytokine secretion in spleen single cell, and tissue resident memory CD4+ T cell (CD4+ TRM cell) in lung tissues. In humoral immunogenicity, GC DTaP vaccines showed high titers for PT and PRN and showed similar patterns in nasal lavage and IL-5 cytokine secretions. The GC DTaP vaccine and the control vaccine showed equivalent results in bacterial clearance after challenge, PTx CHO cell neutralization assay, and CD4+ TRM cell. In contrast, the recombinant raP vaccine exhibited strong antibody responses for FHA and PRN, albeit with low antibody level of PT and low titer in PTx CHO neutralization assay, as compared to control and GC DTaP vaccines. The raP vaccine provided a sterile lung bacterial clearance comparable to a commercial control vaccine after the experimental challenge in murine model. Moreover, raP exhibited a strong cytokine response and CD4+ TRM cell in lung tissue, comparable or superior to the experimental and commercial DTaP vaccinated groups. Contingent on improving the biophysical stability and humoral response to PT, the raP vaccine warrants further development as an effective alternative to aP vaccines for the control of a pertussis outbreak. [ABSTRACT FROM AUTHOR]

Previously developed whole-cell vaccines against Bordetella pertussis, the causative agent of whooping cough, appeared to be too reactogenic due to their endotoxin content. Reduction in endotoxicity can generally be achieved through structural modifications in the lipid A moiety of lipopolysaccharides (LPS). In this study, we found that dephosphorylation of lipid A in B. pertussis through the heterologous production of the phosphatase LpxE from Francisella novicida did, unexpectedly, not affect Toll-like receptor 4 (TLR4)-stimulating activity. We then focused on the inner core of LPS, whose synthesis has so far not been studied in B. pertussis. The kdtA and kdkA genes, responsible for the incorporation of a single 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) residue in the inner core and its phosphorylation, respectively, appeared to be essential. However, the Kdo-bound phosphate could be replaced by a second Kdo after the heterologous production of Escherichia coli kdtA. This structural change in the inner core affected outer-core and lipid A structures and also bacterial physiology, as reflected in cell filamentation and a switch in virulence phase. Furthermore, the eptB gene responsible for the non-stoichiometric substitution of Kdo-bound phosphate with phosphoethanolamine was identified and inactivated. Interestingly, the constructed inner-core modifications affected TLR4-stimulating activity. Whereas endotoxicity studies generally focus on the lipid A moiety, our data demonstrate that structural changes in the inner core can also affect TLR4-stimulating activity. [ABSTRACT FROM AUTHOR]

Background: Pertussis and influenza cause significant morbidity and mortality in pregnancy and the neonatal period. Maternal vaccination in pregnancy would reduce harm, but low vaccine uptake is a concern. This scoping review aimed to understand the reasons for, and approaches, to non-uptake of pertussis and influenza vaccinations in pregnant women in the UK and Ireland. Methods: The inclusion criteria of this scoping review consist of pregnant women who avail of pertussis and influenza vaccines in the UK and Ireland. MEDLINE, EMBASE, Web of Science and CINAHL databases were searched in June 2021 and updated in October 2022. Searches were limited to English language reports published after 2011. We followed the Joanna Briggs Institute guidance on scoping reviews. Data were extracted and charted. Results: Five themes emerged from the literature. Acceptability, as well as organisational and awareness issues, were overarching themes regarding reasons for and approaches to non-uptake of the vaccines respectively. Other themes included healthcare professional factors, information interpretation and pregnancy-related factors. Conclusions: Women need clear, comprehensible information, ideally provided by their healthcare professionals, in a way that is meaningful and addresses their circumstances and risk perceptions. This research will serve as a base for future work that aims behaviour science interventions at the wider pregnant population as well as the target groups that have been identified in this review. [ABSTRACT FROM AUTHOR]

Background Routine childhood vaccination programs have had enormous positive public health impacts worldwide. However, in some areas, these benefits may be impeded by vaccine hesitancy and undervaccination. We estimated the number of reported cases of measles, pertussis, mumps and poliomyelitis averted in Sweden after the introduction of routine childhood vaccination programs. Methods We used annual national data on population size and the number of reported cases of measles (1911–2019), pertussis (1911–2019), mumps (1914–2019) and poliomyelitis (1910–2019) for Sweden. For each disease, we calculated the median and 95% confidence interval of the annual pre-vaccination incidence to estimate the number of counterfactual cases; that is, the estimated number of cases that would have been observed in the post-vaccination period had no vaccine been introduced (median incidence × average annual population). For the post-vaccination periods, we calculated reported cases averted and assumed all decreases were due to vaccines. Results In total, for all four diseases combined, over 2.1 million cases were reported over the respective surveillance periods. Since the introduction of vaccinations, we estimate that over 1.5 million reported cases of these four diseases combined have been averted: measles (633 091), pertussis (608 670), mumps (262 951) and poliomyelitis (58 240). However, due to underreporting, especially during pre-vaccination years, these are likely underestimates. Conclusions Since the introduction of these routine childhood vaccination programs in Sweden, a substantial number of reported cases of vaccine-preventable diseases have been averted. Vigilance against both failure to vaccinate and undervaccination is necessary to prevent future increases of these vaccine-preventable diseases. [ABSTRACT FROM AUTHOR]

Background To reduce the risk of pertussis-related morbidity and mortality in early life, an increasing number of countries recommend maternal pertussis vaccination. However, there is limited knowledge about half-lives of vaccine-induced pertussis-specific maternal antibodies, especially in preterm infants, and factors potentially influencing them. Methods We compared 2 different approaches to provide estimates of the half-lives of pertussis-specific maternal antibodies in infants and explored potential effects on the half-life in 2 studies. In the first approach, we estimated the half-lives per child and used these estimates as responses in linear models. In the second approach, we used linear mixed effect models on a log2 transformed scale of the longitudinal data to use the inverse of the time parameter as an estimate for the half-lives. Results Both approaches provided similar results. The identified covariates partly explain differences in half-life estimates. The strongest evidence we observed was a difference between term and preterm infants, with the preterm infants showing a longer half-life. Among others, a longer interval between vaccination and delivery increases the half-life. Conclusions Several variables influence the decay speed of maternal antibodies. Both approaches have advantages and disadvantages, while the choice is secondary when assessing the half-life of pertussis-specific antibodies. Clinical Trials Registration NCT02408926 and NCT02511327. [ABSTRACT FROM AUTHOR]

Vaccinations for seasonal influenza and pertussis have been recommended for pregnant women in England since 2010 and 2012, respectively. Uptake rates are suboptimal with large regional variations. To improve uptake, from 2016 onwards maternity trusts were commissioned to offer pertussis (and other) vaccinations in addition to these being available in primary care. Since 2021, Covid-19 vaccination has also been recommended for pregnant women. Overall maternal vaccination rates are routinely available, but not the relative provision by maternity trusts. We aimed to describe the national picture of maternity trust provision of maternal vaccinations, including how the maternity trust vaccination programme has progressed. Cross-sectional survey plus comparisons with 2017–18 figures for maternity trust provision of pertussis vaccination, and with UKHSA data for total pertussis vaccination. Twelve NHS commissioners participated (from 13/06/22 to 31/03/23) providing data for 120 (of a total 124) maternity trusts across England. All 120 (100%) trusts were commissioned to deliver influenza, and 107 (89%) to deliver pertussis vaccinations, though not all actually administered the vaccines; 29% offered Covid-19 vaccinations. For 2021–22 we found a mean of 25% (range 0–81.3%) women were vaccinated for pertussis (a large increase compared with previous estimates for 2017–18); and 11% (range 0–74.2%) for influenza, via their maternity trust. Commissioners reported a negative impact of the pandemic on routine vaccination provision. There was indication of efficiency by vaccinating women attending for other appointments. There are diverse mechanisms for reporting pertussis and influenza vaccinations administered at maternity trusts back to primary care, which may be inefficient for maternity staff workload and accuracy of data transfer (especially for pertussis). A high proportion of maternity trusts provide both pertussis and influenza vaccinations, despite a negative impact of the pandemic. Reasons for large between-trust variation in vaccination rates should be explored to improve uptake and equity. [ABSTRACT FROM AUTHOR]

• HCPs play an important role in informing pregnant women about maternal vaccinations. • Strategies to increase MPV uptake should not only focus on providing information. • Decrease experienced barriers in pregnant women that are intended to accept the MPV. In December 2019, the maternal pertussis vaccination (MPV) became part of the Dutch National Immunization Program. This study aims to study MPV behavior and associated psychosocial, attitudinal and organizational factors of pertussis vaccination behavior during pregnancy in the Netherlands. We conducted a cross-sectional survey among pregnant women and recent mothers, up to six months post-partum. The primary outcome measure of this study was MPV behavior. Associations between psychosocial, attitudinal and organizational factors and MPV behavior were assessed using univariate and multivariate binary logistic regression analysis. In total 1348 participants filled out the questionnaire, including 1282 (95.1%) MPV acceptors and 66 (4.9%) MPV refusers. The most important factors associated with MPV behavior were: attitude (aOR: 10.19; 95%CI: 4.30–24.16), outcome expectations (aOR: 8.94; 95%CI: 3.60–22.21), omission bias (aOR: 0.11; 95%CI: 0.02–0.59) and physical accessibility (aOR: 7.44; 95%CI: 3.37–16.46). Pregnant women make their decision about the MPV primarily based on attitudinal and psychosocial factors, such as outcome expectations and attitude. A combination and variation of different messages, about the advantages (effectiveness) and disadvantages (side effects) of maternal vaccination, can be used in reaching pregnant women with a positive and negative attitude about the MPV. In addition, strategies to increase MPV uptake should not only focus on providing information, but also decrease experienced practical barriers, such as poor physical accessibility, in people that are intended to receive the MPV but are not getting vaccinated. [ABSTRACT FROM AUTHOR]

In 2019, maternal pertussis vaccination (MPV) during pregnancy was introduced in the Netherlands. New interventions to promote informed decision making (IDM) about vaccinations are highly needed, especially for new vaccinations. Decision aids (DAs) have the potential to support IDM. This study evaluates the effects of an online DA on IDM and MPV uptake. Pregnant individuals, recruited for the randomized controlled trial (RCT), who gave informed consent (N = 1,236) were randomly assigned to the control (N = 650; no information) or intervention condition (N = 586; DA at 18 weeks pregnancy). MPV uptake and IDM were primary outcomes, decisional certainty and psychological determinants of MPV uptake were secondary outcomes. Measures were taken at 18 weeks of pregnancy (baseline) and at 20 weeks of pregnancy (post-test); intervention use was logged. Data were analysed using intention-to-treat analyses, logistic regression, and linear mixed regression models. Uptake of MPV was high in our sample (92.3 %). No significant effect of the DA condition on MPV uptake was found compared to the control condition. We found that the DA increased IDM (β = 0.24, p <.004) and one of its components level of knowledge about MPV (β = 0.31, p <.004). We also found an increase in decisional certainty (β = 0.24, p <.004), perceived susceptibility (β = 0.24, p <.004), severity of pertussis (β = 0.41, p <.004), and positive affect about MPV (β = 0.15, p <.004). There was a positive association between dose of the intervention and MPV uptake (β = 0.05, p <.004). The DA seemed effective in promoting IDM about and determinants of MPV uptake. No main effect was found on MPV uptake, but MPV uptake was related to the level of exposure to the DA. People with high intentions towards MPV were overrepresented in the sample. However, effects on IDM were consistent among participants with different levels of MPV intention at baseline. [ABSTRACT FROM AUTHOR]

Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory agencies require rabbit pyrogen testing (RPT) for demonstration of vaccine reactogenicity. Recently, the monocyte activation test (MAT) gained popularity as in vitro alternative, yet this assay was primarily designed to test pyrogen-free products. The aim was to adjust the MAT to enable testing of pyrogen containing vaccines in an early stage of development where no reference batch is yet available. The MAT and RPT were compared for assessing unknown safety profiles of pertussis outer membrane vesicle (OMV) vaccine candidates to those of Bexsero as surrogate reference vaccine. Pertussis OMVs with wild-type LPS predominantly activated TLR2 and TLR4 and were more reactogenic than Bexsero. However, this reactogenicity profile for pertussis OMVs could be equalized or drastically reduced compared to Bexsero or a whole-cell pertussis vaccine, respectively by dose changing, modifying the LPS, intranasal administration, or a combination of these. Importantly, except for LPS modified products, reactogenicity profiles obtained with the RPT and MAT were comparable. Overall, we demonstrated that this pertussis OMV vaccine candidate has an acceptable safety profile. Furthermore, the MAT proved its applicability to assess reactogenicity levels of pyrogen containing vaccines at multiple stages of vaccine development and could eventually replace rabbit pyrogen testing. [ABSTRACT FROM AUTHOR]