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Backgrounds:

The presence of maternal transplacental measles antibodies in infants can prevent infection in early life but also suppress the infant response to the first measles vaccine.

Methods

We explored factors associated with antibody levels in mothers and infants at birth, and the decay of antibody in the first year of life in a multicountry seroprevalence study to determine the decay of maternal antibodies and loss of protection, and whether these vary geographically. Stored sera from mothers and infants were shipped to a central laboratory for evaluation of anti-measles IgG by multiplex immunoassay and plaque reduction neutralisation titres (PRNT). Data from the first five countries were available for analysis (Mali, Thailand, The Netherlands, UK, Vietnam)

Log-transformed data were compared using linear models adjusting for country. Decay models included polynomial terms and infant level random intercepts to account for the repeated timepoints.

Results:

Higher measles serum IgG and PRNT were statistically associated with maternal age, in both maternal samples (IgG p=0.001, PRN p=0.003) and cord blood (IgG p=0.037, PRN p=0.015). Maternal age was also statistically significantly related to the WHO measles vaccine coverage during the mother’s year of birth, indicating that older mothers are less likely to have been vaccinated in early life than younger mothers resulting in higher antibody in later life from childhood infection.

Measles IgG and PRNT in infant samples decayed at a similar rate across all countries in the first 6 months of life. Average PRNT were below protective thresholds (120 mIU/ml) by 6 months of age for all countries. For anti-measles IgG, all countries had seronegative estimates at 9 months of age.

Conclusions/Learning Points:

Infants older than 6 months are susceptible to measles infection. These results can inform vaccination programmes.

Backgrounds:

Despite high-quality evidence from randomized clinical trials conducted in low-middle income countries showing efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age, assessments of effectiveness in settings with different influenza seasonality and across multiple seasons are limited.

Methods

We conducted a test-negative study using population-based Ontario laboratory data to identify all influenza virus tests (in any clinical setting) among infants <6 months of age during 9 influenza seasons (2010-11 to 2018-19). These data were linked with health administrative data to ascertain information on maternal-infant dyads, including whether women had been vaccinated against influenza during pregnancy. Vaccine effectiveness (VE) was estimated from the adjusted odds ratio for vaccination, computed using logistic regression with adjustment for maternal age, infant age at test, season of conception, prenatal care adequacy, neighbourhood income, and influenza season. Women who received influenza vaccination less than 14 days prior to obstetric delivery or received the previous season’s vaccine were treated as unvaccinated.

Results:

Among 23,806 infants <6 months of age who were tested for influenza virus, 1,783 (7.5%) tested positive. Overall, 2,168 (9.1%) of infants were born to women vaccinated against influenza during pregnancy; 1,708 (7.2%) remained when those vaccinated less than 14 days before delivery or with the previous season’s influenza vaccine were reclassified as unvaccinated. Across seasons, the adjusted effectiveness of influenza vaccination during pregnancy against laboratory-confirmed infant influenza infection prior to 6 months of age was 64% (95% confidence interval: 51% to 74%).

Conclusions/Learning Points:

Since infants <6 months are at high risk for serious influenza-related illness, but not eligible for influenza vaccination, immunization during pregnancy is an effective strategy for protecting young infants during their first influenza season.

Backgrounds:

Young children infected with Ebola have high mortality. A heterologous two-dose vaccine regimen (Ad26.ZEBOV [Ad26], MVA-BN-Filo [MVA]) was investigated in infants.

Methods

Healthy infants (4-11 months) in Sierra Leone and Guinea were randomised in a double-blind study to receive Ad26, MVA or Meningococcal Group A, C, W135, Y conjugate vaccine (MenACWY) 56 days apart. Adverse events (AEs) were assessed following each vaccine dose. Serious AEs (SAEs) were assessed from informed consent signing until six months post-dose 2. Binding antibody concentrations against EBOV GP were measured by FANG ELISA at baseline, 21 days post-dose 2, and one year post-dose 1.

Results:

A total of 108 infants underwent randomisation: 75 with Ad26, MVA and 33 with MenACWY. The vaccine regimen was well tolerated. The safety profile consisted of mild-to-moderate AEs, with the most common solicited AEs being irritability, decreased appetite, and pyrexia ≥38°C. Pyrexia was more frequent with Ad26, MVA versus control. The frequency of unsolicited AEs was similar in the Ad26, MVA and control groups. No SAEs were related to either vaccine. Strong humoral immune responses were observed in all infants who received the Ad26, MVA vaccine regimen at 21 days post-dose 2 and persisted up to one year in 96% of participants.

Conclusions/Learning Points:

The Ad26, MVA Ebola vaccine regimen was well tolerated, induced strong antibody responses in infants, and is suitable for preventing Ebola in infant populations. Binding antibody responses were comparable to levels previously reported in African children (1-3 years) and higher than the response in older children and adults.

Backgrounds:

We aim to assess whether a switch to non-G1P[8] strains and greater strain diversity post-rotavirus vaccine introduction is associated with vaccination or due to natural fluctuations in strain types across Europe.

Methods

The study area includes 23 countries submitting data to either EuroRotaNet or the WHO EURO Sentinel Surveillance Network for Rotavirus. Epidemiological and microbiological data was collected on genotyped rotavirus-positive samples between 2006 and 2018.

To investigate the effect of vaccination on strain types we will fit Bayesian multinomial logistic regression models, with genotype as the outcome. Generalized linear mixed-effect models will be used to analyse the effect of vaccination on strain diversity and richness.

Results:

Descriptive analysis of EuroRotaNet countries

In the twelve countries contributing to EuroRotaNet, 62,773 samples were characterised during the study period. Seven genotypes contributed 97% of single rotavirus strain typed specimens: G1P[8]; G4P[8]; G2P[4]; G9P[8]; G3P[8]; G12P[8]; and G9P[4]. Since the introduction of routine vaccination in the UK and Germany in 2013 the prevalence of G1P[8] has fallen (Figure 1). In the UK the prevalence of G2P[4] has increased since vaccine introduction, peaking at 79% in 2016/17. However, in 2017/18 in the UK the strain distribution was more diverse, and G3P[8] accounted for 24% of single typed strains. In countries without widespread rotavirus vaccination, there has been a shift since 2015/16 to non-G1P[8] genotypes.

Conclusions/Learning Points:

The consistent decline in G1P[8] strains across both countries with and without infant rotavirus immunization schedules may suggest either that the increase in vaccinated cohorts across Europe is having an impact across borders or that natural fluctuations in strain distributions have coincided with increased rotavirus vaccination across Europe. The statistical analyses are in progress and will allow us to elucidate firmer conclusions.

Backgrounds:

Respiratory syncytial virus (RSV), a leading cause of viral lower respiratory tract illness (LRTI) in young children, is associated with significant morbidity, especially during their first year of life. Nirsevimab is an investigational long-acting antibody developed to prevent medically attended RSV-LRTI (RSV MALRTI). The objective of this work was to explore public health and economic impact of a strategy that immunizes all Spanish infants experiencing their first RSV season with nirsevimab compared to current standard of practice (SoP).

Methods

A static decision analytic model was developed that tracks the whole Spanish infant cohort, by month of birth, during their first RSV season and considers the different possible RSV-related health outcomes and their associated costs. Impact of nirsevimab was modelled, considering an efficacy of 79.5% in term and preterm infants (based on a pooled analysis from Phase IIb [preterm infants] and MELODY Phase III [term infants] studies), and non-inferiority in palivizumab-eligible infants. An immediate onset of protection, and 5 months of protection were assumed.

Results:

The model estimated these cases avoided: 8,201 hospitalisations, including 872 intensive care cases, 24,420 emergency department visits, as well as 93,209 primary care visits and 9 deaths over one season. The associated annual economic savings were estimated at €29.8 million in healthcare costs and €2.3 million in lost productivity, without considering the cost of preventive passive immunization alternatives (Table 1). The largest reduction in events and costs was seen in preterm and term infants. Additionally, reduction in heath events provided by nirsevimab impacted infants born out of season in a 2-to-1 ratio compared to infants born in season.

Conclusions/Learning Points:

Immunization of all infants experiencing their first RSV season with nirsevimab is likely to result in thousands of RSV cases avoided versus current SoP.

This study was funded by Sanofi Pasteur, Spain

Backgrounds:

We have previously identified 4 immunoreactive, linear B-cell epitopes within pneumococcal surface proteins (CbpD, PhtD, PhtE & ZmpB) that are highly conserved among different serotypes. These epitopes, emulsified in Freund’s Adjuvant, showed high immunogenicity and offered prolonged survival against murine pneumococcal sepsis. Herein, they were incorporated in SVLPs to improve survival rates and induce robust humoral immune responses without the need for external adjuvants.

Methods

Female BALB/c mice were subcutaneously immunized thrice at three-week intervals with synthetic 20mer peptides displayed on the surface of SVLPs. Positive controls received PCV13, while negative controls received the SVLP-carrier alone. Pneumococcal lethal sepsis was induced by 10⁶ CFUs of an intraperitoneally administered serotype 3 clinical strain and survival was monitored. Sera were collected one day prior the second and third immunization and before the pneumococcal challenge. Antibody responses were assessed using ELISA.

Results:

Mice actively immunized with SVLP-conjugated synthetic peptides demonstrated enhanced survival against pneumococcal sepsis, compared to controls (p=0.005-0.04, Wilcoxon test). Five days after infection the survival rate was 100% for the positive control (PCV13), 66.7% for PhtE, 33.3% for CbpD, 16.7% for ZmpB and 0% for PhtD and the negative control (SVLPs), respectively. All immunized mice produced high levels of peptide-specific IgG antibodies. The difference in the endpoint titers, compared to controls, was statistically significant (p=0.0001-0.03, unpaired t-test). All immunized mice elicited gradually higher antibody titers upon receiving the booster immunizations.

Conclusions/Learning Points:

SVLP-conjugated synthetic epitopes are able to confer prolonged survival, compared to controls, associated with robust humoral immune responses. Further experiments are needed to assess the protective efficacy of the epitopes with the most promising characteristics in order for them to be considered as candidate antigens for novel pneumococcal vaccine formulations.

Backgrounds:

The objective of this study is to investigate if Tissue resident memory T cells (TRM) cells specific for Bordetella pertussis (B.pertussis) are identifiable in human adeno-tonsillar tissue and to determine the impact of acellular or whole cell pertussis vaccination in childhood on the frequency of antigen-specific TRM cells.

Methods

Twenty study participants undergoing elective tonsillectomy were recruited, 10 of whom received the acellular pertussis (aP) vaccine in childhood (<25 years of age) and 10 of whom received the whole cell pertussis (wP) vaccine. Operative tonsil tissue, venous blood and nasopharyngeal swab (B. pertussis culture and PCR) will be collected from each participant. Tonsil and blood mononuclear cells were isolated and cultured with a panel of B. pertussis antigens and antigen-specific cytokine producing TRM were identified via flow cytometry.

Results:

We have identified IFN-γ and/or IL-17-producing CD69⁺CD103^- and CD69⁺CD013⁺ CD4⁺ T_RM cells in human adeno-tonsillar tissue, but not in peripheral blood, which were expanded by culture with sonicated B. pertussis (SBP) and filamentous haemagglutinin (FHA). Adults who received whole cell pertussis vaccination during routine childhood immunisation had significantly more IFN-γ producing CD69+ TRM following stimulation with SBP and FHA than aP vaccinated individuals (p<0.05).

Conclusions/Learning Points:

Our study demonstrates that in humans, whole cell pertussis vaccination during routine childhood immunsiaiton but not acellular pertussis vaccine induces a population of antigen specific-cytokine producing TRM cells in tonsillar tissue that persist up to 30 years following initial vaccination. In the murine model, these cells in the nose and lung have been associated with protection against colonisation following B. pertussis aerosol challenge. Immunisation strategies that aim to generate a population of protective TRM cells at mucosal site of infection are therefore more likely to induce more effective and sustained protective immunity.

Backgrounds:

The pertussis resurgence calls for new vaccines. Recombinant acellular pertussis (aP_gen) vaccines containing 5µg of genetically detoxified Pertussis Toxin (Pe_on) and 5 µg Filamentous Hemagglutinin (FHA) are licensed in Singapore and Thailand. The safety and immunogenicity of recombinant reduced dose ap-2,5 (2µg PT_gen, 5µg FHA) or combined to tetanus and diphtheria (Tdap-2,5) are compared to a chemically detoxified PT (Tdap_chem) vaccine.

Methods:

A phase 2/3, randomized controlled, observer-blind trial aimed at demonstrating the non-inferior immunogenicity in 450 adolescents aged 9-17 years at two sites in Thailand. The participants were enrolled in 1:1:1 to receive ap-2,5, Tdap-2,5 or Tdap_chem vaccine. Seroconversion rate, defined as the 4-fold increase of anti-PT and anti-FHA IgG, was compared at Day 28 after vaccination and in a subset of participants at Day 336. At Day 28 after vaccination, non-inferiority was reached if the lower limit of the 95% CI of difference in seroconversion rate was higher than the non-inferiority margins (-10%).The superiority can also be concluded if the difference in seroconversion rates lied above zero.

Results:

From June to August 2019, 450 adolescents with median age of 12 years were enrolled. Seroconversion rates were statistically significant higher in ap-2,5 and Tdap-2,5 than in Tdap_chem group for ELISA anti-PT, after 1 month: 93% (95% CI 88-97), 94% (90-98) and 70% (63-78) respectively(P ≤ 0.05); and after 1 year: 73% (61-86), 56% (42-70) and 16% (6-26)(P ≤ 0.05). Similar findings were found for anti-FHA. Both non-inferiority and superiority of ap_gen and Tdap_gen vaccines vs Tdap_chem vaccine were met. No vaccine-related serious adverse event was reported.

Conclusions/Learning Points:

Both recombinant reduced dose ap_gen and Tdap_gen vaccines were safe and able to induce high and persisting pertussis antibody response.

Backgrounds:

Mexico’s early childhood pertussis immunization schedule consists of 4 doses, given at 2, 4, 6, and 18 months of age. A European-manufactured whole-cell pertussis (wP) vaccine was used in 2000-2007. Since 2008, 2-component acellular pertussis vaccines (2aP) have been used. This study estimated the effectiveness of 3 or 4 doses of the two vaccine types used in Mexico between 2000 and 2019.

Methods:

Pertussis cases among 6.5-48.5-month-olds reported over 2000-2019, their vaccination status and diagnosis confirmation type (clinical, laboratory or Epilink) were obtained from the Mexican National pertussis surveillance system. Vaccine coverage rates were derived from Mexico’s CeNSIA and CONAPO databases. Vaccine effectiveness (VE) was estimated using the screening method.

Results:

Comparable VE estimates were observed in the wP (2000-2007) and 2aP (2008-2019) vaccines periods, ranging from 94 to 97%, after either 3 or 4 doses, and regardless of the case-definition used (all notifications vs laboratory-confirmed only).

Conclusions/Learning Points:

Over the 11-year period of their use, the pentavalent and hexavalent 2aP vaccines used in Mexico demonstrated as strong protective effectiveness as the previously used wP vaccine, ensuring protection from pertussis among vaccinated children at least up to the age of a scheduled school-entry booster. Maintaining high vaccination coverage rates is essential in preventing and controlling pertussis.