A decade of norovirus disease risk among older adults in upper-middle and high income countries: a systematic review.

BACKGROUND: Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) causing both sporadic and outbreak-associated illness. Norovirus (NoV) infections occur across all ages but certain sub-groups are considered at increased risk due to heightened transmission and/or symptom severity. Older adults are potentially at high risk of NoV-associated illness due to frequent outbreaks in long-term care facilities (LTCFs) and severe health outcomes following infection. Elucidation of NoV risk among older adults will support prevention, treatment and control efforts. METHODS: We conducted a systematic literature review to summarize the published risk estimates of NoV-associated illness, hospitalization and death among individuals aged 65 years and older. A structured search using defined NoV and gastroenteritis (GE) terms was performed in the PubMed and EMBASE databases of human studies published between January 1, 2003 and May 16, 2013. RESULTS: We identified 39 studies from high income (HI) and upper-middle income (UMI) countries. Thirty-six percent of publications provided risk estimates based on laboratory-confirmed or epidemiologically-linked population-based surveillance data using molecular diagnostic methods. Over the study period, estimated annual NoV rates and extrapolated number of cases among older adults in HI and UMI countries were: 29-120/10,000 or 1.2-4.8 million NoV-associated illnesses; 18-54/10,000 or 723,000-2.2 million NoV-associated outpatient visits; 1-19/10,000 or 40,00-763,000 NoV-associated inpatient visits; 0.04-0.32/10,000 or 2000-13,000 NoV-associated deaths. NoV was responsible for approximately 10-20 % of GE hospitalizations and 10-15 % of all-cause GE deaths among older adults. Older adults experienced a heightened risk of nosocomial infections. Those in LTCFs experience frequent NoV outbreaks and the range in attack rates was 3-45 %, case hospitalization rates 0.5-6 % and case fatality rates 0.3-1.6 %. CONCLUSIONS: Older adults are at increased risk of severe NoV-associated health outcomes. NoV-associated hospitalization rates were higher, more severe, resulted in longer stays and incurred greater costs than for younger patients. NoV-associated mortality rates were approximately 200 % higher among individuals 65 years and older compared to <5 years. The burden of NoV among older adults is expected to rise along with societal aging and increased need for institutionalized care. NoV prevention in older adults, including potential vaccination, may significantly impact risk of severe illness.

Neonatal vaccination with an acellular pertussis vaccine accelerates the acquisition of pertussis antibodies in infants.

OBJECTIVES: Because young infants are at highest risk of pertussis complications, this study assessed whether neonatal acellular pertussis (aP) vaccination could provide earlier immunity. STUDY DESIGN: Neonates (n = 121) were randomly assigned (1:1) to receive either aP or hepatitis B vaccine (HBV) (controls) vaccine at birth, followed by vaccination with DTaP-HBV-IPV/Hib at 2, 4 and 6 months. Immune responses were measured. Reactogenicity was assessed for 7 days after each dose. RESULTS: The aP birth dose was followed by few adverse events. Reactogenicity of subsequent vaccine doses did not differ between groups. Seven serious adverse events were reported from each group; none were related to the study vaccines. At 3 months of age, vaccination with aP at birth had induced significantly higher antibody responses to the 3 pertussis antigens compared with controls. At 7 months, geometric mean/concentrations of antibodies against pertussis antigens were similar in both groups, and all subjects had reached "seroprotective" antibody concentrations against diphtheria, tetanus, and poliovirus types 1, 2, and 3. Geometric mean/concentrations of antibodies to haemophilus influenzae type b (Hib) and HBV were significantly lower in the aP group. CONCLUSIONS: Early neonatal immunization with aP was safe, well tolerated, and resulted in earlier antibody responses, seen after the first dose of a DTaP combination vaccine. Birth dose of aP did not induce immunologic tolerance to pertussis antigens but appear to dampen responses to Hib and HBV vaccines.

Immunogenicity and reactogenicity of acellular pertussis booster vaccines in children: standard pediatric versus a reduced-antigen content formulation.

Booster vaccination with a reduced-antigen-content dTpa, pediatric DTPa or adult Td vaccine in DTPa-primed children aged 4-6 years was evaluated. Immunogenicity and CMI was assessed one month and 3.5 years after vaccination. Symptoms were solicited for 15 days post-vaccination. There were no differences between groups in diphtheria or tetanus seroprotection or pertussis vaccine-response rates. Anti-diphtheria and anti-PRN concentrations were higher after DTPa, but groups differences reduced over time. Non-significant trends toward reduced reactogenicity of dTpa were observed. Many factors influence vaccine choice at preschool age. The dTpa vaccine was as immunogenic and possibly better tolerated than DTPa at this age.

Immunity to pertussis 5 years after booster immunization during adolescence.

BACKGROUND: We conducted a 5-year follow-up study on the persistence of pertussis-specific antibody and cell-mediated immunity after booster immunization of adolescents aged 11-13 years with a tricomponent acellular pertussis vaccine (Boostrix; trials diphtheria-tetanus-acellular pertussis [Tdap]-004/030). METHODS: Cellular and humoral immunity to pertussis toxin (PT), filamentous hemagglutinin, and pertactin were measured in adolescents (age, 16 years) 5 years after booster immunization. Similar investigations were performed for control adolescents who had received only diphtheria and tetanus booster vaccination. RESULTS: Five years after pertussis booster vaccination, the geometric mean concentrations of immunoglobulin G (IgG) elicited by each of the 3 pertussis vaccine antigens decreased from 1-month and 3-year postvaccination levels, but with the exception of PT IgG, were still higher than the prevaccination levels. PT IgG levels were undetectable in 28% of the subjects, but 44% of those subjects still tested positive for cell-mediated immunity to PT. Filamentous hemagglutinin IgG and pertactin IgG levels were significantly higher in Tdap-boosted adolescents than in the control subjects. Antibody concentrations at 1 month after vaccination strongly predicted antibody persistence. Cell-mediated immunity levels to PT, filamentous hemagglutinin, and pertactin persisted above the prebooster levels measured 5 years earlier. CONCLUSIONS: The results of the present study of adolescents indicate that the interval between acellular pertussis booster immunizations might be extended beyond 5 years.

Is there a need for a new generation of vaccines against pertussis?

Current vaccines against pertussis have proved their safety and efficacy in large-scale clinical trials. Despite high vaccination coverage, pertussis is still prevalent and increasing, probably as a result of waning immunity. Addition of new antigens, such as adenylate cyclase, to current vaccines might improve some aspects of the immune response to vaccination, but are unlikely to significantly increase the duration of protection. Intranasal, oral and DNA pertussis vaccines are some way from clinical development, although one live attenuated, intranasal pertussis vaccine may soon enter Phase I trials. In the meantime, the potential of currently available safe and efficacious pertussis vaccines should be maximised. Rationalisation of pertussis boosters in childhood and introduction of widespread repeat booster vaccination in adolescents and adults would already lessen disease prevalence and morbidity among susceptible infants.

Combined diphtheria-tetanus-pertussis vaccine for tetanus-prone wound management in adults.

INTRODUCTION: Booster vaccination against tetanus, diphtheria and pertussis is recommended throughout life. Adults are difficult to reach and vaccination coverage in this group is often inadequate. The use of a reduced-antigen content combined diphtheria-tetanus-acellular pertussis ('adult' dTpa) vaccine for tetanus prophylaxis in emergency room wound management provides an opportunity to boost immunity against three infections simultaneously, thereby optimizing the efficiency of medical interventions with adults assessed. METHODS: A single-blind, randomized, controlled study of 320 healthy adults, the anti-tetanus antibody response within 10 days following vaccination with Boostrix (reduced-antigen diphtheria-tetanus-acellular pertussis). RESULTS: The anti-tetanus antibody response to the reduced-antigen diptheria-tetanus-acellular pertussis vaccine was equivalent to Tetavax, a licensed monovalent tetanus-toxoid vaccine. CONCLUSION: The use of diphtheria-tetanus-acellular pertussis is a safe and effective way to provide vaccination to adults against three diseases during emergency room visits for wound management.

Pertussis-specific cell-mediated and humoral immunity in adolescents 3 years after booster immunization with acellular pertussis vaccine.

We evaluated pertussis-specific cell-mediated immunity (CMI) and humoral immunity in adolescents 3 years after they received an acellular pertussis booster immunization. Two hundred sixty-four adolescents were examined for immunoglobulin G antibodies, and 49 were examined for CMI against Bordetella pertussis antigens 40 months after receiving the booster. A control group of similarly aged adolescents who had received diphtheria and tetanus vaccination 3 years earlier was included for comparison. Pertussis-specific CMI persisted at greater than prebooster immunization levels. Although they had decreased by the 3-year follow-up, antibody levels remained significantly higher than prebooster immunization levels. Antibodies against pertussis antigens and CMI against filamentous hemagglutinin and pertactin were significantly higher in vaccinated adolescents than in control subjects. The acellular pertussis booster immunization provides long-term CMI and humoral immunity lasting for >or=3 years. The significantly higher immunity observed in the diphtheria, tetanus, and acellular pertussis vaccine recipients, compared with that in control subjects, indicates that these responses are more likely to have resulted from the booster immunization than from the boosting effects of natural B. pertussis infection.

The burden of childhood pneumonia in the developed world: a review of the literature.

BACKGROUND: Estimates of the disease burden from childhood pneumonia are available for most developed countries, but they are based mainly on models. Measured country-specific pneumonia burden data are limited to a few nations and differ in case definitions and case ascertainment methods. This review describes pneumonia disease burden in developed countries. METHODS: We reviewed studies describing childhood pneumonia incidence in North America, Europe, Australia, New Zealand and Japan. Available estimates suggest that each year in developed countries there are up to 2.6 million cases of pneumonia, including 1.5 million hospitalized cases and around 3000 pneumonia deaths (compared with approximately 640 annual deaths from meningitis) in children <5 years of age. RESULTS: Data to inform policy decisions would be improved by information on burden and etiology of severe pneumonia, population-based incidence of ambulatory visits and hospitalizations and prevalence of complications and sequelae.

Carriage of Neisseria meningitidis in Europe: a review of studies undertaken in the region.

Meningococcal conjugate vaccines induce herd protection by preventing nasopharyngeal meningococcal acquisition, which is a prerequisite for invasive disease. Thus, meningococcal carriage epidemiology is important in understanding relationships between carriage and disease. A literature search traced information on meningococcal carriage in 27 EU countries. Meningococcal carriage prevalence differed within and between countries, varying across age groups, serogroup distribution and over time. Carriage prevalence increased during childhood, peaking in 15-24-year-olds. While serogroup B was usually the dominant serogroupable carried serogroup, serogroups C, W-135 and Y were also frequently carried. Current carriage studies in Europe are limited. New studies using standardized methods are needed to improve our understanding of meningococcal disease etiology and transmission, and to monitor the impact of meningococcal conjugate vaccines in populations.

Booster vaccination and 1-year follow-up of 4-8-year-old children with a reduced-antigen-content dTpa-IPV vaccine.

Reduced-antigen-content pertussis vaccines designed initially for booster vaccination of adolescents and adults can also be used to vaccinate pre-school age children. Combination vaccines, which reduce the number of administered injections, combine multiple antigens including inactivated poliovirus (IPV), which is recommended in this age group in some countries. This randomised, controlled study compared a combined diphtheria-tetanus-acellular pertussis-inactivated polio-containing booster vaccine, dTpa-IPV (Boostrix Polio, n=822), to separately administered dTpa (Boostrix) and IPV (IPV Mérieux, n=136) in 4-8-year-old children who had previously received four doses of DTPa. Additional serological assessment was performed 1 year after the booster dose. One month after vaccination, seroprotection/vaccine response rates were similar for both groups. At least 99.9% of the subjects had protective antibodies against diphtheria, tetanus and polio, and at least 90.1% had a vaccine response to pertussis antigens after dTpa-IPV. Reactogenicity of dTpa-IPV was comparable to dTpa + IPV. Fever and grade 3 loss of appetite occurred more commonly after dTpa-IPV, whereas swelling and grade 3 pain occurred more frequently after separately administered dTpa + IPV (P<0.05 for all). However, 95% CIs overlapped in all cases. Large swelling reactions after dTpa-IPV occurred less commonly than have been reported after a fifth dose of DTPa. One year after the booster, 98.6% of the subjects tested continued to have protective antibodies against diphtheria, tetanus and polio, and at least 81.2% were seropositive for pertussis components. The reduced-antigen-content dTpa-IPV vaccine was immunogenic, well tolerated and safe in pre-school age children. It provides immunity against four diseases in a single injection, with the potential reactogenicity benefit of a reduced-antigen dose.

Immunogenicity of a single dose of reduced-antigen acellular pertussis vaccine in a non-vaccinated adolescent population.

German adolescents (n=123) without previous pertussis vaccination, no history of pertussis and low IgG-anti-pertussis-toxin (PT) levels received one dose of the Tdap vaccine Boostrix. Blood samples were taken before, and 5-12 days and 29-49 days after vaccination. IgG- and IgA-anti-PT, IgG- and IgA-anti filamentous hemagglutinin, IgG-anti-pertactin, IgG-anti-tetanus-toxin, and IgG-anti-diphtheria-toxin were measured by ELISA. 88.6% of subjects had an immune response to PT, and all vaccinees had an immune response to at least one pertussis antigen 29-49 days after vaccination. IgA-anti-PT and IgA-anti-FHA responses were found in 43 and 81% of subjects, respectively. This study shows that in unvaccinated German adolescents pertussis immunity can be achieved by a single dose of Tdap.

Combined reduced-antigen-content diphtheria-tetanus-acellular pertussis and polio vaccine (dTpa-IPV) for booster vaccination of adults.

Many countries recommend diphtheria, tetanus and/or poliomyelitis boosters in adolescents or adults and the need for pertussis booster vaccination beyond childhood is increasingly recognized. A new combined reduced-antigen-content dTpa-IPV vaccine provides booster vaccination against all four diseases in one single injection. The immunogenicity and safety of the dTpa-IPV vaccine was compared to that of licensed dTpa+IPV or Td-IPV vaccines in 806 adolescents >14 years of age and adults with a heterogeneous vaccination history. The dTpa-IPV vaccine was immunogenic and well tolerated. No clinically significant differences were observed between groups. Anti-tetanus antibody kinetics indicated that each of the vaccines could be used for tetanus prophylaxis in acute wound management. For all vaccines, the lowest post-vaccination antibody concentrations were observed in subjects >40 years of age, those seronegative prior to vaccination and those subjects whose last vaccination was > or =20 years ago. In conclusion, dTpa-IPV vaccination of subjects over 14 years of age was as immunogenic and well tolerated as the licensed dTpa+IPV or Td-IPV vaccines. Vaccination coverage of adults is poor and the use of combined vaccines such as dTpa-IPV during vaccination visits, or for wound management, maximizes opportunities for boosting in these difficult to reach age groups.

Reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and inactivated polio vaccine as a booster for adolescents 10 to 14 years of age.

UNLABELLED: High rates of pertussis disease in adolescents suggest that additional boosting against pertussis would be beneficial. A combined acellular-pertussis-containing booster vaccine (dTpa-IPV; Boostrixtrade mark Polio, n =440) was compared to separately administered dTpa (Boostrixtrade mark) and inactivated polio virus (IPV; Imovax Polio((R)), n =219), and to DTPa-IPV (Infanrixtrade mark IPV, n =111) vaccine in a partially blind, randomised controlled trial in 10-14 year olds. One month after vaccination, seroprotection/seropositivity rates for all antigens were similar for all groups. Although pertussis and diphtheria antibody geometric mean antibody concentrations were higher after DTPa-IPV, all subjects had protective antibodies against diphtheria, tetanus and polio, and at least 97% had a vaccine response to pertussis antigens. Reactogenicity of dTpa-IPV was comparable to dTpa + IPV, but dTpa-IPV was generally better tolerated than DTPa-IPV. CONCLUSION: The combined reduced-antigen-content-diphtheria-tetanus-acellular-pertussis and IPV vaccine is immunogenic and well tolerated when administered to adolescents and could be used to improve the control of pertussis disease in this age group.

A new DTPw-HBV/Hib vaccine is immunogenic and safe when administered according to the EPI (Expanded Programme for Immunization) schedule and following hepatitis B vaccination at birth.

New combination vaccines and reliable sources of vaccine components are essential to ensure the success of mass immunisation programmes in the 21st century. We evaluated a new combined diphtheria-tetanus-whole-cell-pertussis-hepatitis B vaccine, extemporaneously mixed with a Haemophilus influenzae type b conjugate vaccine (DTPw-HBV/Hib) containing 2.5 microg PRP in 913 Philippino infants, administered according to the EPI schedule at 6, 10 and 14 weeks of age after a birth dose of hepatitis B vaccine (HBV; trial DTPw-HBV/Hib-001). One month after the third dose of DTPw-HBV/Hib (N = 182), 99.4% and 94.2% of subjects had anti-PRP antibody levels > or =0.15 microg/mL and > or =1.0 microg/mL, respectively. In addition, 95.9%, 100.0% and 87.6% of subjects had seroprotective antibody concentrations against diphtheria, tetanus and hepatitis B, respectively. The seroprotection rate to hepatitis B increased significantly to 94.3% in subjects who received a dose of HBV at birth. The pertussis vaccine response rate was > or =95%. Seroprotection/vaccine response rates to all antigens after DTPw-HBV/Hib were at least as good as those observed after vaccination with GSK Biologicals' licensed Tritanrix HepB/Hiberix (containing 10 microg PRP) which was used as comparator. Although redness >20 mm in diameter and fever > or = 37.5 degrees C (axillary route) occurred more often after the new DTPw-HBV/Hib vaccine (p < 0.05), other Grade 3 adverse events occurred similarly between the groups. The new DTPw-HBV/Hib vaccine was as immunogenic and well tolerated as the licensed control vaccine when administered according to the immunologically challenging EPI schedule. A birth dose of HBV is important to maximize protection against hepatitis B in endemic regions where the EPI schedule is in place.

Macrolides in cystic fibrosis: is there a role?

A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen. Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF. Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored. Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF. Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term.

Anti-diphtheria antibody seroprotection rates are similar 10 years after vaccination with dTpa or DTPa using a mathematical model.

The reduced antigen content diphtheria, tetanus and pertussis (dTpa) vaccine (Boostrixtrade mark) has been shown to induce a strong booster response to all the vaccine components in 4-6 year olds. However, anti-diphtheria antibody levels were observed to be lower when compared to the "full strength" paediatric DTPa vaccine. To assess the impact of this difference on long-term protection, a mathematical model was developed to predict diphtheria antibody decay over time. The model was based on a linear decrease in log-transformed antibody concentrations after the first year post-vaccination. When applied to data collected 3.5 years after vaccination of 4-6 year olds with either DTPa or dTpa, the model predicted that 10 years post-vaccination, 98.6% of subjects vaccinated with dTpa were likely to remain seroprotected against diphtheria, compared to 99.6% vaccinated with DTPa. Therefore, the difference observed in diphtheria antibody geometric mean concentrations 1 month after booster vaccination at 4-6 years with dTpa or DTPa is unlikely to be of clinical relevance 10 years later at the time of the adolescent booster.

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine.

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N=310, Td+pa group N=77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.