Manifesto on the Value of Adult Immunization: "We Know, We Intend, We Advocate".

Immunization through vaccination is a milestone achievement that has made a tremendous contribution to public health. Historically, immunization programs aimed firstly to protect children, who were disproportionally affected by infectious diseases. However, vaccine-preventable diseases can have significant impacts on adult mortality, health, and quality of life. Despite this, adult vaccinations have historically been overlooked in favor of other health priorities, because their benefits to society were not well recognized. As the general population is aging, the issue of vaccination in older adults is gaining importance. In high-income countries, recommendations for the routine vaccination of older adults have been gradually introduced. The Italian National Immunization Plan is considered to be among the most advanced adult vaccination plans in Europe. However, available data indicate there is low adherence to vaccination recommendations in Italy. The COVID-19 pandemic has exposed the damage that can be caused by an infectious disease, especially among adults and individuals with comorbidities. The aim of this "Manifesto", therefore, is to provide an overview of the existing evidence on the value of adult vaccination, in the Italian context, with a call to action to healthcare providers and health authorities.

Hepatitis A antibody persistence 8 and 10 years after 1-dose and 2-dose vaccination in children from Panama.

BACKGROUND: Hepatitis A virus (HAV) remains a global public health concern, which is potentially growing in Latin America, due to an expected shift from high to intermediate endemicity levels. The use of HAV vaccines in pediatric national immunization programs (NIPs), either as a 2-dose or a 1-dose schedule, has been explored in Latin American countries; however, evidence demonstrating long-term protection in this population is limited in the region. We evaluated long-term antibody persistence following a 1-dose partial series and the recommended 2-dose schedule used in Panama's pediatric NIP. METHODS: Two independent cross-sectional serological surveys were conducted at year 8 (Y8) and Y10 following vaccination under the NIP with 1 or 2 doses of an inactivated HAV vaccine (Havrix, GSK). Seropositivity (anti-HAV antibody concentration ≥ 15 mIU/mL) rates and antibody geometric mean concentrations (GMCs) were assessed at each serosurvey. Non-inferiority of 1 dose versus 2 doses was also explored. RESULTS: This study (NCT02712359) included 600 and 599 children at Y8 and Y10 post-vaccination, respectively. Seropositivity rates were 74.3% (95% confidence interval [CI]: 69.0; 79.2) and 97.7% (95% CI: 95.3; 99.1) at Y8 and 71.9% (95% CI: 66.4; 76.9) and 96.3% (95% CI: 93.5; 98.2) at Y10, in the 1-dose and 2-dose groups, respectively. Antibody GMCs were lower in the 1-dose versus the 2-dose group in both surveys. Non-inferiority was not demonstrated since the lower limit of the 2-sided 95% CI for the between-group difference in seropositivity rates (1-dose minus 2-dose) was < -10%. CONCLUSION: Anti-HAV antibody persistence was observed in lower percentages of children receiving 1 dose versus 2 doses of Havrix, at 8 and 10 years post-vaccination in Panama. Further investigations are needed to confirm antibody persistence and conclude on the protection afforded beyond 10 years in the pediatric population in Latin America.

Hepatitis A epidemiology in Latin American countries: a 2020 view from a systematic literature review.

INTRODUCTION: The World Health Organization recommends vaccination against hepatitis A virus (HAV) for children aged 1 year and older in areas where endemicity has shifted from high to intermediate. There are no recent comprehensive reviews of the epidemiology of HAV infection in Latin America, but seroprevalence and socioeconomic data suggest that, with improved clean water and sanitation systems, countries are transitioning to intermediate endemicity. AREAS COVERED: We conducted a systematic literature review of the epidemiology of HAV infection in 25 countries in the Latin American region, which included gray literature. We compiled data on HAV incidence and prevalence, including the identification of epidemiological changes observed in countries that established pediatric HAV vaccination programs. EXPERT OPINION: We identified 59 relevant articles, including 34 peer-reviewed seroprevalence studies (12 recent studies from Brazil), three incidence studies, and six vaccine impact studies (three from Argentina). Based on the estimated age at midpoint of population immunity in each country, most have a high-intermediate, intermediate, or low-intermediate level of HAV endemicity, suggesting that national childhood immunization may be an appropriate disease prevention strategy. However, recent data were lacking for most countries. Improved data quality and continued epidemiological surveillance are required for this region.

Perceptions of tick-borne encephalitis risk: a survey of travellers and travel clinics from Canada, Germany, Sweden and the UK.

Background: While the worldwide endemicity of tick-borne encephalitis (TBE) has been increasing, a lack of awareness of the risks of this life-threatening disease may be leading to an underutilization of preventive measures among travellers to TBE-endemic regions. This study's objectives were to assess travellers' awareness of TBE and advice-seeking attitudes, and to evaluate practices of travel clinics regarding pre-travel advice. Methods: We used an online questionnaire to identify individuals aged 18-65 years residing in the UK, Germany, Canada and Sweden, who had travelled to TBE-endemic countries between 2013 and 2016. This sample was defined as the visit-risk sample. Of these, the first 375 respondents who reported that they had engaged in pre-defined at-risk activities (e.g. hiking in forests) were asked to complete an additional online survey and were included in the activity-risk sub-sample. We also used an online/phone questionnaire to interview travel clinic personnel. Results: The TBE visit-risk sample included 4375 individuals; 69% had heard of the disease and 32% had heard of a TBE vaccine. Before travelling, travellers most commonly sought information online (26%); fewer travellers consulted family doctors (8%) or travel clinics (5%). In the activity-risk sample, 79% of the travellers were aware of at least one correct TBE prevention measure; however, only 15% reported being vaccinated within the past 3 years, with 11% of vaccinated travellers doing so following a clinic's recommendation. One hundred and eighty travel clinic representatives responded and reported that TBE vaccination was recommended to an average of 61% of travellers to endemic regions. Vaccination-reminder services such as follow-up appointments, e-mail and text reminders were offered by 50% of the clinics. Conclusions: There is a need to increase awareness of the risk and prevention of TBE among travellers to endemic countries, and travel clinics could play an important role in this process. 5975671594001tay062media15975671594001.

Perceptions of rabies risk: a survey of travellers and travel clinics from Canada, Germany, Sweden and the UK.

Background: Extensive global experience shows that rabies pre-exposure prophylaxis (PrEP) through vaccination is effective and well tolerated, yet many travellers opt not to be vaccinated when travelling to rabies-endemic countries. Previous research has identified several factors influencing the choices travellers make to reduce the risk of rabies, including cost, time constraint and perspective on the importance of vaccination. The objectives of this study were to assess travellers' awareness of rabies and advice-seeking attitudes and to evaluate travel clinics practices regarding rabies pre-travel advice. Methods: We surveyed individuals aged 18-65 years residing in the UK, Germany, Canada and Sweden who had travelled to rabies-endemic countries between 2013 and 2016 and defined this as the rabies visit-risk sample. The first 850 respondents from the visit-risk sample who had undertaken pre-defined at-risk activities (e.g. contact with animals during the trip) completed an additional 15-min online questionnaire and were included in the activity-risk subsample. We also interviewed travel clinic personnel using a 25-min online or phone questionnaire. Results: The visit-risk sample included 4678 individuals. Many sought pre-travel health information online (33%) or talked to a family doctor (24%). Within the activity-risk subsample, 83% of travellers were aware of at least a few basic facts about rabies, and 84% could identify at least one correct rabies prevention measure; 49% were aware of a rabies vaccine, however, only 8% reported receiving PrEP vaccination within the past 3 years. Among 180 travel clinic respondents, 21% reported recommending PrEP against rabies to all travellers to rabies-endemic countries. Travel clinics estimated that 81% of travellers complete their travel vaccination schedules and reported sending reminders by e-mails (38%), text (38%), phone calls (37%) or by using vaccination cards (37%). Conclusions: These findings suggest that although travellers had frequently heard of rabies, awareness of the risks of this serious infectious disease was relatively low. 5975671594001tay062media15975671594001.

Post-exposure prophylaxis (PEP) for rabies with purified chick embryo cell vaccine: a systematic literature review and meta-analysis.

INTRODUCTION: Fifteen million people each year receive post-exposure prophylaxis (PEP) to prevent rabies, yet the disease remains neglected and highly under-reported. AREAS COVERED: In this systematic literature review, we assessed the immunogenicity, efficacy, and safety of a purified chick embryo cell-culture rabies vaccine (PCECV) for PEP against rabies by intramuscular (IM) or intradermal (ID) administration. We performed meta-analyses to compare immunogenicity according to the route of vaccine administration, study population, and PEP regimen, such as number of doses, and concomitant rabies immunoglobulin. EXPERT COMMENTARY: There were 54 estimates of immune responses to vaccination, which showed that in the overall population, after starting PEP with PCECV by the IM or ID route (≥2.5 IU per dose), almost all individuals had rabies virus neutralizing antibody (RVNA) titers above the World Health Organization (WHO) recommended serological threshold for an adequate immune response to vaccination (RVNA ≥0.5 IU/ml by day 14). In the overall population, PCECV had an acceptable safety profile. However, given that there are 59,000 human rabies deaths reported annually, the challenge is to improve access to PCECV for PEP against human rabies.

Systematic literature review comparing rapid 3-dose administration of the GSK tick-borne encephalitis vaccine with other primary immunization schedules.

INTRODUCTION: Tick-borne encephalitis (TBE), which is endemic across large regions of Europe and Asia, is most effectively prevented through vaccination. Three-dose primary TBE vaccination schedules are either rapid (0,7,21-days) or conventional (0,28-84-days, 9-12-months). The second dose can also be administered at 14 days for faster priming and sero-protection). Areas covered: We used a three-step selection process to identify 21 publications comparing the immunogenicity and/or safety of different schedules. Expert commentary: Priming with two or three TBE vaccine doses was highly immunogenic. After conventional priming (0-28 days), 95% adults and ≥95% children had neutralization test (NT) titers ≥10 at 14 days post-dose-2 compared with 92% adults and 99% children at 21 days post-dose-3 (rapid schedule). Most subjects retained NT titers ≥10 at day 300. A single booster dose induced a strong immune response in all subjects irrespective of primary vaccination schedule or elapsed time since priming. GMT peaked at 42 days post-dose-1 (i.e., 21 days post-dose 3 [rapid-schedule], or 14-28 days post-dose-2 [conventional-schedule]), and declined thereafter. Adverse events were generally rare and declined with increasing doses. In the absence of data to recommend one particular schedule, the regimen choice will remain at the physician's discretion, based on patient constraints and availability.

The immunogenicity and safety of GSK's recombinant hepatitis B vaccine in adults: a systematic review of 30 years of experience.

INTRODUCTION: Engerix B (GSK HepB, GSK, Belgium) was the first recombinant hepatitis B virus vaccine to be licensed, and marked its 30th anniversary in 2016. Vaccination of adult populations against HBV is usually implemented on a risk-based approach with varying degrees of success. Confirmation of ongoing vaccine effectiveness requires monitoring the performance of HBV immunization as reported in individual studies, using systematic methods. Areas covered: We conducted a systematic review of the literature to summarize 30 years of immunogenicity and safety data for GSK HepB in adult populations. Expert commentary: Primary 3-dose vaccination of healthy individuals is generally associated with seroprotection rates of 90% or more, although seroprotection decreases with older age. Accelerated 0, 1, 2-month or 0, 7 and 21-day schedules require the recommended booster dose to achieve similar rates of seroprotection. Lower rates of seroprotection were also observed in adults with underlying chronic disease and with a weakened immune system. GSK HepB had a clinically acceptable safety profile in all of the populations studied, including individuals with underlying co-morbidities and immunosuppression. GSK HepB will continue to contribute to global HBV control for the foreseeable future. Further investigation is needed into how to optimize seroprotection in less immune-competent groups.

The immunogenicity of GSK's recombinant hepatitis B vaccine in children: a systematic review of 30 years of experience.

INTRODUCTION: The World Health Organization recommends hepatitis B virus (HBV) vaccines to be included in national immunization schedules everywhere, and has adopted the strategic goal of halting viral hepatitis as a major public health threat by 2030, under which vaccination plays a major role. Engerix™ B (GSK HepB, GSK, Belgium) was the first recombinant HBV vaccine to be licensed, and marked its 30th anniversary in 2016. Areas covered: We conducted a systematic review of the literature summarizing 30 years of immunogenicity and safety data for GSK HepB in children and adolescents. Expert commentary: Primary 3-dose vaccination of healthy infants and children, including infants born to HBsAg-positive mothers, using the standard 0, 1, 6 month schedule was associated with seroprotection rates ≥96.0%. In high-risk infants, vaccine efficacy at year 5 was 96.0% after 3-dose priming in infancy and immunoglobulin at birth. Lower seroprotection rates were observed in children with severe underlying disease including human immunodeficiency virus infection and cancer. GSK HepB had a clinically acceptable safety profile in all of the populations studied. HBV vaccines have demonstrated long-term impacts on rates of fulminant hepatitis, chronic liver disease and hepatocellular carcinoma. GSK HepB will continue to contribute to global HBV control for the foreseeable future.

Modeling the hepatitis A epidemiological transition in Brazil and Mexico.

BACKGROUND: Many low- to middle-income countries have completed or are in the process of transitioning from high or intermediate to low endemicity for hepatitis A virus (HAV). Because the risk of severe hepatitis A disease increases with age at infection, decreased incidence that leaves older children and adults susceptible to HAV infection may actually increase the population-level burden of disease from HAV. Mathematical models can be helpful for projecting future epidemiological profiles for HAV. METHODS: An age-specific deterministic, dynamic compartmental transmission model with stratification by setting (rural versus urban) was calibrated with country-specific data on demography, urbanization, and seroprevalence of anti-HAV antibodies. HAV transmission was modeled as a function of setting-specific access to safe water. The model was then used to project various HAV-related epidemiological outcomes in Brazil and in Mexico from 1950 to 2050. RESULTS: The projected epidemiological outcomes were qualitatively similar in the 2 countries. The age at the midpoint of population immunity (AMPI) increased considerably and the mean age of symptomatic HAV cases shifted from childhood to early adulthood. The projected overall incidence rate of HAV infections decreased by about two thirds as safe water access improved. However, the incidence rate of symptomatic HAV infections remained roughly the same over the projection period. The incidence rates of HAV infections (all and symptomatic alone) were projected to become similar in rural and urban settings in the next decades. CONCLUSION: This model featuring population age structure, urbanization and access to safe water as key contributors to the epidemiological transition for HAV was previously validated with data from Thailand and fits equally well with data from Latin American countries. Assuming no introduction of a vaccination program over the projection period, both Brazil and Mexico were projected to experience a continued decrease in HAV incidence rates without any substantial decrease in the incidence rates of symptomatic HAV infections.

Impact of universal mass vaccination with monovalent inactivated hepatitis A vaccines - A systematic review.

The WHO recommends integration of universal mass vaccination (UMV) against hepatitis A virus (HAV) in national immunization schedules for children aged ≥1 year, if justified on the basis of acute HAV incidence, declining endemicity from high to intermediate and cost-effectiveness. This recommendation has been implemented in several countries. Our aim was to assess the impact of UMV using monovalent inactivated hepatitis A vaccines on incidence and persistence of anti-HAV (IgG) antibodies in pediatric populations. We conducted a systematic review of literature published between 2000 and 2015 in PubMed, Cochrane Library, LILACS, IBECS identifying a total of 27 studies (Argentina, Belgium, China, Greece, Israel, Panama, the United States and Uruguay). All except one study showed a marked decline in the incidence of hepatitis A post introduction of UMV. The incidence in non-vaccinated age groups decreased as well, suggesting herd immunity but also rising susceptibility. Long-term anti-HAV antibody persistence was documented up to 17 y after a 2-dose primary vaccination. In conclusion, introduction of UMV in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of hepatitis A in vaccinated and in non-vaccinated age groups alike.

Pre-travel advice, attitudes and hepatitis A and B vaccination rates among travellers from seven countries†.

BACKGROUND: Knowledge about the travel-associated risks of hepatitis A and B, and the extent of pre-travel health-advice being sought may vary between countries. METHODS: An online survey was undertaken to assess the awareness, advice-seeking behaviour, rates of vaccination against hepatitis A and B and adherence rates in Australia, Finland, Germany, Norway, Sweden, the UK and Canada between August and October 2014. Individuals aged 18-65 years were screened for eligibility based on: travel to hepatitis A and B endemic countries within the past 3 years, awareness of hepatitis A, and/or combined hepatitis A&B vaccines; awareness of their self-reported vaccination status and if vaccinated, vaccination within the last 3 years. Awareness and receipt of the vaccines, sources of advice, reasons for non-vaccination, adherence to recommended doses and the value of immunization reminders were analysed. RESULTS: Of 27 386 screened travellers, 19 817 (72%) were aware of monovalent hepatitis A or combined A&B vaccines. Of these 13 857 (70%) had sought advice from a healthcare provider (HCP) regarding combined hepatitis A&B or monovalent hepatitis A vaccination, and 9328 (67%) were vaccinated. Of 5225 individuals eligible for the main survey (recently vaccinated = 3576; unvaccinated = 1649), 27% (841/3111) and 37% (174/465) of vaccinated travellers had adhered to the 3-dose combined hepatitis A&B or 2-dose monovalent hepatitis A vaccination schedules, respectively. Of travellers partially vaccinated against combined hepatitis A&B or hepatitis A, 84% and 61%, respectively, believed that they had received the recommended number of doses. CONCLUSIONS: HCPs remain the main source of pre-travel health advice. The majority of travellers who received monovalent hepatitis A or combined hepatitis A&B vaccines did not complete the recommended course. These findings highlight the need for further training of HCPs and the provision of reminder services to improve traveller awareness and adherence to vaccination schedules.

HAV & HBV vaccination among travellers participating in the National Health and Wellness Survey in five European countries.

BACKGROUND: A main cause of hepatitis A and B infections in European countries is travel to endemic countries. Most research on hepatitis vaccination among travellers from Europe has been conducted in airports or travel clinics, samples which potentially overrepresented frequent travellers. METHODS: 2102 respondents across France, Germany, Italy, Spain, and UK completed an internet-based questionnaire. Vaccination status, travel to endemic countries, and other characteristics were compared across frequent, occasional, and non-travellers. Logistic regressions tested association between vaccination and travel adjusting for potential confounders. RESULTS: Most respondents were occasional travellers (61%) and 24% were frequent travellers. Frequent travellers had 2.3-2.4 times the odds of being vaccinated relative to non-travellers, and odds of vaccination were 2.5-3.1 times higher among travellers to endemic areas relative to others (all p < .05). Frequent travellers were more aware of their vaccination status (HAV: 80% vs. 72%; HBV: 82% vs. 74%), though many who were vaccinated could not identify the number of injections to complete the series (47% vs. 29%) (all p < .05). CONCLUSION: Travel frequency and destination endemicity are associated with increased hepatitis A and B vaccination. The number of unvaccinated travellers and the lack of recall for the dosing schedule suggest the need to improve travellers' awareness and adherence to recommendations.

Immunogenicity, effectiveness and safety of combined hepatitis A and B vaccine: a systematic literature review.

BACKGROUND: Hepatitis A and B are two of the most common vaccine-preventable diseases and vaccination for Hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for those at risk of contracting HAV and/or HBV through their occupation, travel or lifestyle. OBJECTIVE: To describe the vaccine efficacy, immunogenicity, effectiveness and safety of the combined vaccine against hepatitis A and hepatitis B. METHODS: A systematic review of the literature published between 1990 and 2015. RESULTS: Anti-HAV seropositivity rates ranged from 96.2% to 100% and anti-HBs seroprotection rates from 82% to 100%. Antibodies persisted up to 15 years and geometric mean concentration (GMC) remained above the seropositivity cut-off value for both. Anti-HAV and anti-HBs immune responses were lower in less immunocompetent individuals one month after completion of the immunization schedule. The safety profiles of Twinrix(TM) and monovalent hepatitis A and B vaccines were similar. CONCLUSION: The vaccine offers satisfactory long-term immunogenicity rates, expected duration of protection and safety profile similar to the monovalent hepatitis A or B vaccines.

Modeling the hepatitis A epidemiological transition in Thailand.

BACKGROUND: In most low- and middle-income countries, hepatitis A virus (HAV) is shifting or expected to shift from high endemicity to intermediate or low endemicity. A decreased risk of HAV infection will cause an increase in the average age at infection and will therefore increase the proportion of infections that results in severe disease. Mathematical models can provide insights into the factors contributing to this epidemiological transition. METHODS: An MSLIR compartmental dynamic transmission model stratified by age and setting (rural and urban) was developed and calibrated with demographic, environmental, and epidemiological data from Thailand. HAV transmission was modeled as a function of urbanization and access to clean drinking water. The model was used to project various epidemiological measures. RESULTS: The age at midpoint of population immunity remains considerably younger in rural areas than in urban areas. The mean age of symptomatic hepatitis A infection in Thailand has shifted from childhood toward early adulthood in rural areas and is transitioning from early adulthood toward middle adulthood in urban areas. The model showed a significant decrease in incidence rates of total and symptomatic infections in rural and urban settings in Thailand over the past several decades as water access has increased, although the overall incidence rate of symptomatic HAV is projected to slightly increase in the coming decades. CONCLUSIONS: Modeling the relationship between water, urbanization, and HAV endemicity is a novel approach in the estimation of HAV epidemiological trends and future projections. This approach provides insights about the shifting HAV epidemiology and could be used to evaluate the public health impact of vaccination and other interventions in a diversity of settings.

Travel-associated disease among US residents visiting US GeoSentinel clinics after return from international travel.

BACKGROUND: US residents make 60 million international trips annually. Family practice providers need to be aware of travel-associated diseases affecting this growing mobile population. OBJECTIVE: To describe demographics, travel characteristics and clinical diagnoses of US residents who present ill after international travel. METHODS: Descriptive analysis of travel-associated morbidity and mortality among US travellers seeking care at 1 of the 22 US practices and clinics participating in the GeoSentinel Global Surveillance Network from January 2000 to December 2012. RESULTS: Of the 9624 ill US travellers included in the analysis, 3656 (38%) were tourist travellers, 2379 (25%) missionary/volunteer/research/aid workers (MVRA), 1580 (16%) travellers visiting friends and relatives (VFRs), 1394 (15%) business travellers and 593 (6%) student travellers. Median (interquartile range) travel duration was 20 days (10-60 days). Pre-travel advice was sought by 45%. Hospitalization was required by 7%. Compared with other groups of travellers, ill MVRA travellers returned from longer trips (median duration 61 days), while VFR travellers disproportionately required higher rates of inpatient care (24%) and less frequently had received pre-travel medical advice (20%). Illnesses of the gastrointestinal tract were the most common (58%), followed by systemic febrile illnesses (18%) and dermatologic disorders (17%). Three deaths were reported. Diagnoses varied according to the purpose of travel and region of exposure. CONCLUSIONS: Returning ill US international travellers present with a broad spectrum of travel-associated diseases. Destination and reason for travel may help primary health care providers to generate an accurate differential diagnosis for the most common disorders and for those that may be life-threatening.

A prospective, observational, epidemiological evaluation of the aetiology and antimicrobial susceptibility of acute otitis media in Saudi children younger than 5years of age.

BACKGROUND: Information regarding acute otitis media (AOM) aetiology is important for developing effective vaccines. Here, bacterial aetiology and antimicrobial susceptibility of AOM were determined in young Saudi children. METHODS: Children aged 3-60months with a new episode of AOM, who had not received antibiotics or had received antibiotics for 48-72h but remained symptomatic, were enrolled in this prospective, observational, epidemiological study in Riyadh. Middle ear fluid (MEF) samples were collected by tympanocentesis or from spontaneous otorrhea, and tested for the presence of Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes and Moraxella catarrhalis. Antimicrobial susceptibility of the identified pathogens was assessed using E-tests. RESULTS: Between June 2009 and May 2011, 66 children were enrolled. S. pneumoniae was detected in 6 episodes and non-typeable H. influenzae (NTHi) in 8 episodes. Moreover, Staphylococcus aureus, which is an uncommon cause of AOM, was detected in 17 episodes. Pneumococcal serotypes were 7F (n=2), 23F (n=2), 19F (n=1) and 15F (n=1). Susceptibility to cefotaxime was observed in all pneumococcal and H. influenzae isolates, to cefuroxime in 4/6 pneumococcal and 8/8 H. influenzae isolates, and to penicillin in 5/6 pneumococcal isolates. CONCLUSIONS: S. pneumoniae and NTHi were major bacterial contributors for AOM in Saudi children.

Microbiology of bacteria causing recurrent acute otitis media (AOM) and AOM treatment failure in young children in Spain: shifting pathogens in the post-pneumococcal conjugate vaccination era.

OBJECTIVE: To prospectively identify the bacterial aetiology and antimicrobial susceptibility of problematic (recurrent and treatment failure) acute otitis media in Spanish children several years after the introduction of 7-valent pneumococcal conjugate vaccine. METHODS: Tympanocentesis or careful sampling of spontaneous otorrhoea was performed on children aged 3 to <36 months with recurrent acute otitis media, acute otitis media treatment failure or unresolved acute otitis media. RESULTS: 105 acute otitis media episodes (77 sampled by tympanocentesis, 28 otorrhoea samples) were evaluated: 46 recurrent, 35 treatment failures, 24 unresolved acute otitis media. 74 episodes (70.4%) had at least one bacterium identified on culture: Streptococcus pneumoniae was identified in 21 episodes, Haemophilus influenzae (all non-typeable) in 44, Streptococcus pyogenes in 2, Moraxella catarrhalis in 2. No statistically significant difference in bacterial aetiology by episode type was detected. Non-typeable H. influenzae was the most commonly isolated pathogen in all acute otitis media types and in all age sub-groups. Forty percent of S. pneumoniae isolates were multi-drug resistant. Pneumococcal serotype 19A was the most frequently identified serotype (7/21 episodes). Multi-drug resistance was found in 56% of 19A isolates. Of non-typeable H. influenzae isolates, 15% were ampicillin resistant and 13% were amoxicillin/clavulanate resistant. S. pneumoniae and non-typeable H. influenzae DNA were each detected in 57% of samples culture negative for these pathogens, including 12 co-infections. CONCLUSION: Combining culture and polymerase chain reaction results, H. influenzae and S. pneumoniae may be implicated in 70% and 43% of clinically problematic bacterial acute otitis media episodes, respectively. The impact of new vaccines to prevent both S. pneumoniae and non-typeable H. influenzae acute otitis media may be substantial in this population and is worth investigating.