High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Seroepidemiology of pertussis in Huzhou: A population-based, cross-sectional study.

PURPOSE: The resurgence of pertussis has occurred around the world. However, the epidemiological profiles of pertussis cannot be well understood by current diseases surveillance. This study was designed to understand the seroepidemiological characteristics of pertussis infection in the general population of Huzhou City, evaluate the prevalence infection of pertussis in the population, and offer insights to inform adjustments in pertussis prevention and control strategies. METHODS: From September to October 2023, a cross-sectional serosurvey was conducted in Huzhou City, involving 1015 permanent residents. Serum samples were collected from the study subjects, and pertussis toxin IgG antibodies (Anti-PT-IgG) were quantitatively measured using enzyme-linked immunosorbent assay (ELISA). The analysis included the geometric mean concentration (GMC) of Anti-PT-IgG, rates of GMC≥40IU/mL, ≥100IU/mL, and <5IU/mL. Stratified comparisons were made based on age, vaccination history, and human categories. RESULTS: Among the 1015 surveyed individuals, the geometric mean concentration (GMC) of Anti-PT-IgG was 10.52 (95% CI: 9.96-11.11) IU/mL, with a recent infection rate of 1.58%, a serum positivity rate of 11.43%, and a proportion with <5IU/mL of 40.49%. Among 357 children with clear vaccination history, susceptibility decreased with an increasing number of vaccine doses (Z = -6.793, P < 0.001). The concentration of Anti-PT-IgG exhibited a significant post-vaccination decline over time (Z = -5.143, P < 0.001). In women of childbearing age, the GMC of Anti-PT-IgG was 7.71 (95% CI: 6.90-8.62) IU/mL, with no significant difference in susceptibility among different age groups (χ2 = 0.545, P = 0.909). The annual pertussis infection rate in individuals aged ≥3 years was 9321 (95%CI: 3336-16039) per 100,000, with peak infection rates in the 20-29, 40-49, and 5-9 age groups at 34363 (95%CI: 6327-66918) per 100,000, 22307.72 (95%CI: 1380-47442) per 100,000, and 18020(95%CI: 1093-37266) per 100,000, respectively. CONCLUSIONS: In 2023, the actual pertussis infection rate in the population of Huzhou City was relatively high. Vaccine-induced antibodies exhibit a rapid decay, and the estimated serum infection rate increases rapidly from post-school age, peaking in the 20-29 age group. It is recommended to enhance pertussis monitoring in adolescents and adults and refine vaccine immunization strategies.

Severe pertussis in infants: a scoping review.

BACKGROUND: Pertussis (Whooping Cough) is a respiratory infection caused by Bordetella pertussis. Pertussis usually occurs in childhood; severe infections are most common in infants. It can be fatal with severe complications such as pulmonary hypertension, heart failure, and encephalitis. OBJECTIVES: We sought to synthesize the existing literature on severe pertussis in infants and inform further study. METHODS: A scoping review was performed based on the methodological framework developed by Arksey & O'Malley. Search in Pubmed and Embase databases, with no restrictions on the language and date of publication. RESULTS: Of the 1299 articles retrieved, 64 were finally included. The selected articles were published between 1979 and 2022, with 90.6% (58/64) of the studies in the last two decades. The studies covered epidemiology, pathology, clinical characteristics, risk factors, treatments, and burden of disease. CONCLUSION: The literature reviewed suggests that studies on severe pertussis in infants covered a variety of clinical concerns. However, these studies were observational, and experimental studies are needed to provide high-quality evidence.

Seroprevalence of IgG antibodies against pertussis toxin in the Chinese population: A systematic review and meta-analysis.

Pertussis is a vaccine-preventable infectious disease; however, data on pertussis antibody levels in a nationwide population are still limited in China. We aimed to pool the seropositivity rates of IgG antibodies against pertussis toxin (PT-IgG) across the country. We systematically searched PubMed, Web of Science, Embase, and the China National Knowledge Infrastructure Database for studies published between January 1, 2010, and June 30, 2023. Studies reporting the seroprevalence of PT-IgG among a healthy Chinese population were included. Pooled estimates were obtained using random-effects meta-analyzes. The meta-analysis included 39 studies (47,778 participants) reporting anti-PT IgG seropositivity rates. The pooled rate for all ages was 7.06% (95% CI, 5.50%-9.07%). Subgroup analyzes showed rates ranging from 6.36% to 12.50% across different age groups. This meta-analysis indicated a low anti-PT IgG seropositivity rate in the Chinese population, particularly among school-aged children and young adults. This finding underscores the urgent need to refine immunization strategies.

Economic burden of pertussis in children: A single-center analysis in Hangzhou, China.

The "reemergence of pertussis" has elicited international concerns, occurring paradoxically amidst the expansion of immunization programs. This study was aimed to evaluate quantitatively the economic burden and identify the determinants that influence the cost associated with treating pertussis in Chinese children. We evaluated the economic burden by Chinese children diagnosed with pertussis at the Children's Hospital, Zhejiang University School of Medicine in 2022. Direct medical expenses and the utilization of medical resources attributed to pertussis were calculated. A generalized linear regression model was applied to analyze the determinants that were associated with the direct medical expenses among patients. Among the 1110 pertussis patients included in the study, 1060 were outpatients and 50 were inpatients. The average direct medical cost was ¥1878.70(i.e. $279.33). Living in urban areas (OR:1.27, p = .04), complications (OR:1.40, p < .001), hospitalization (OR:10.04, p < .001), and ≥ 3 medical visits (OR:3.71, p < .001) were associated with increased direct medical expenses. Having received four doses of the pertussis vaccine was associated with reduced direct medical expenses (OR:0.81, p = .04). This study underscores a substantial economic burden of pertussis in Hangzhou, with pronounced implications for patients residing in urban areas, experiencing complications, requiring hospitalization, having multiple medical consultations, or lacking comprehensive pertussis vaccination.

fim3-24/ptxP-3 genotype is associated to whooping cough outbreak in Brazilian Midwest: The selection of Bordetella pertussis strains driven by vaccine immunization.

Whopping cough (or Pertussis) is an acute infectious respiratory disease caused by Bordetella pertussis bacteria. The disease is highly transmissible and can be fatal in children under two years old. Since the introduction of vaccine immunization in 1940, Pertussis incidence decreased worldwide. In Brazil, the immunization was introduced in 1977 using the whole cell (wP) vaccine. Despite the high vaccination coverage, an unexpected increase in the number of observed Pertussis cases was observed in 2012. In this year, 2257 cases were reported exceeding the average incidence rate of <1000 cases per year until 2010. This outbreak reached a peak level in 2014 and ended in 2018 according to the Brazilian National Surveillance System (SINAN). To understand the relationship between the outbreak and the vaccination, bacterial isolates (n = 136) from the Brazilian Midwest region obtained during the outbreak were submitted to genotyping of two vaccine loci: ptxP and fim3. Most of isolates (102) were obtained from nursing children (29 days to 2 years old). Genotyping of 94 isolates revealed that fim3-24/ptxP-3 was the most prevalent genotype (68%) associated with the outbreak peak. Two additional genotypes were also observed: fim3-1/ptxP-3 (15%) and fim3-3/ptxP-3 (17%). Conversely, the fim3-1/ptxP-2 genotype, which is harbored by the strain used in the wP vaccine (Bp137), was not observed. These results showed that B. pertussis circulating strains in the outbreak analyzed were different from the strain used for Pertussis immunization in Brazil. These observations provide insights that could be used to target vaccination programs to prevent future whooping cough outbreaks in Brazil.

[Guidelines for diagnosis and management and prevention of pertussis of China (2024 edition)].

Pertussis re-emergence is a global public health concern. The reported incidence of pertussis in China from 2018 to 2022 was comparable to that in the late 1980s. In fact, the incidence of pertussis is still significantly underestimated in China, owing to a lack of comprehensive active pertussis surveillance, missed diagnosis of atypical pertussis cases, and the fact that many medical institutions do not perform pertussis laboratory diagnosis. Meanwhile, China is also faced with the clinical issue that Bordetella pertussis is highly resistant to first-line macrolide treatment. To better guide and standardize the clinical diagnosis, treatment, monitoring, prevention and control of pertussis cases in China, a multidisciplinary guideline development group comprised of experts in infectious diseases, epidemiology, immunization planning and guideline methodology proposed 12 clinical issues related to the diagnosis, treatment and prevention, especially vaccine immunization strategies from a practical perspective. Through research question construction, evidence retrieval and synthesis, evidence appraisal and evidence-to-decision discussion, recommendations and implementation suggestions were formulated to provide references for clinical physicians engaged in the diagnosis and management of pertussis, microbiological laboratory professionals, hospital infection control professionals, and public health professionals involved in infectious disease prevention, control and immunization planning.

Pertussis epidemic in Denmark, August 2023 to February 2024.

We report a record high pertussis epidemic in Denmark since August 2023. Highest incidence was in adolescents, while peak incidence in infants was lower vs previous epidemics in 2019 and 2016. Among infants aged 0-2 months, over half (29/48) were hospitalised and one infant died, underlining the disease severity in the youngest. To protect infants, pertussis vaccination in pregnant women was introduced in January 2024 in the national vaccination programme. Improved vaccination surveillance in pregnant women is being implemented.

Outer membrane vesicles derived from Bordetella pertussis are potent adjuvant that drive Th1-biased response.

For several years, we have been committed to exploring the potential of Bordetella pertussis-derived outer membrane vesicles (OMVBp) as a promising third-generation vaccine against the reemerging pertussis disease. The results of our preclinical trials not only confirm its protective capacity against B. pertussis infection but also set the stage for forthcoming human clinical trials. This study delves into the examination of OMVBp as an adjuvant. To accomplish this objective, we implemented a two-dose murine schedule to evaluate the specific immune response induced by formulations containing OMVBp combined with 3 heterologous immunogens: Tetanus toxoid (T), Diphtheria toxoid (D), and the SARS-CoV-2 Spike protein (S). The specific levels of IgG, IgG1, and IgG2a triggered by the different tested formulations were evaluated using ELISA in dose-response assays for OMVBp and the immunogens at varying levels. These assays demonstrated that OMVBp exhibits adjuvant properties even at the low concentration employed (1.5 µg of protein per dose). As this effect was notably enhanced at medium (3 µg) and high concentrations (6 µg), we chose the medium concentration to determine the minimum immunogen dose at which the OMV adjuvant properties are significantly evident. These assays demonstrated that OMVBp exhibits adjuvant properties even at the lowest concentration tested for each immunogen. In the presence of OMVBp, specific IgG levels detected for the lowest amount of antigen tested increased by 2.5 to 10 fold compared to those found in animals immunized with formulations containing adjuvant-free antigens (p<0.0001). When assessing the adjuvant properties of OMVBp compared to the widely recognized adjuvant alum, we detected similar levels of specific IgG against D, T and S for both adjuvants. Experiments with OMVs derived from E. coli (OMVE.coli) reaffirmed that the adjuvant properties of OMVs extend across different bacterial species. Nonetheless, it's crucial to highlight that OMVBp notably skewed the immune response towards a Th1 profile (p<0.05). These collective findings emphasize the dual role of OMVBp as both an adjuvant and modulator of the immune response, positioning it favorably for incorporation into combined vaccine formulations.

Factors associated with pregnant women's willingness to receive maternal pertussis vaccination in Guizhou Province, China: An exploratory cross-sectional study.

The rise in pertussis incidence among infants in Guizhou, China underscores the need for maternal acellular pertussis vaccine (aP) immunization, a key strategy in protecting infants from severe health consequences. However, the willingness of pregnant women in Guizhou to receive this vaccine is not well-understood. This study aimed to explore pregnant women's intentions toward maternal pertussis vaccination in Guizhou and identify the associated factors. A questionnaire based on the health belief model, was administered in an exploratory cross-sectional study from January to February 2022. Data from 564 participants were collected and analyzed. The chi-square test, Mann-Whitney U test, and Poisson regression were used to identify potential factors associated with vaccination intentions. Participants' median age was 27 y (interquartile range (IQR): 24-31), and the median number of children per participant was one. The study found that only 36.0% of the participants intended to receive the aP vaccine while 64.0% were uncertain or negative in this regard. Significant factors associated with intentions to vaccinate included perceived barriers and cues for action and perceived benefits. The major barriers for low vaccination intentions were safety concerns for both the fetus and the mother, and family members' negative attitudes. Free vaccines, perceiving preventive benefits, observing other pregnant women getting vaccinated, and healthcare provider recommendations may facilitate vaccination intentions. Multiple immune strategies should be developed or optimized to cope with the resurgence of pertussis.

Reduced pertussis disease severity in infants following the introduction of pertussis vaccination of pregnant women in Spain, 2015-2019.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Vaccination during pregnancy and modulation of IgG response to pertussis vaccines in infants: The impact of different vaccine formulations.

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.

Effectiveness of one and two doses of acellular pertussis vaccines against laboratory-confirmed pertussis requiring hospitalisation in infants: Results of the PERTINENT sentinel surveillance system in six EU/EEA countries, December 2015 - December 2019.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

BECC438b TLR4 agonist supports unique immune response profiles from nasal and muscular DTaP pertussis vaccines in murine challenge models.

The protection afforded by acellular pertussis vaccines wanes over time, and there is a need to develop improved vaccine formulations. Options to improve the vaccines involve the utilization of different adjuvants and administration via different routes. While intramuscular (IM) vaccination provides a robust systemic immune response, intranasal (IN) vaccination theoretically induces a localized immune response within the nasal cavity. In the case of a Bordetella pertussis infection, IN vaccination results in an immune response that is similar to natural infection, which provides the longest duration of protection. Current acellular formulations utilize an alum adjuvant, and antibody levels wane over time. To overcome the current limitations with the acellular vaccine, we incorporated a novel TLR4 agonist, BECC438b, into both IM and IN acellular formulations to determine its ability to protect against infection in a murine airway challenge model. Following immunization and challenge, we observed that DTaP + BECC438b reduced bacterial burden within the lung and trachea for both administration routes when compared with mock-vaccinated and challenged (MVC) mice. Interestingly, IN administration of DTaP + BECC438b induced a Th1-polarized immune response, while IM vaccination polarized toward a Th2 immune response. RNA sequencing analysis of the lung demonstrated that DTaP + BECC438b activates biological pathways similar to natural infection. Additionally, IN administration of DTaP + BECC438b activated the expression of genes involved in a multitude of pathways associated with the immune system. Overall, these data suggest that BECC438b adjuvant and the IN vaccination route can impact efficacy and responses of pertussis vaccines in pre-clinical mouse models.

Interventional study to improve pertussis and influenza vaccination uptake in pregnant women.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.