Three-dose Schedule Research Articles

Summary of the National Advisory Committee on Immunization's Update on the recommended human papillomavirus (HPV) vaccine immunization schedule.

Human papillomavirus (HPV) infections are the most common sexually transmitted infections. In the absence of vaccination, it is estimated that 75% of sexually active Canadians will have a sexually transmitted HPV infection at some point in their lives. Canada's National Advisory Committee on Immunization (NACI) has recommended a three-dose immunization schedule with HPV vaccine for females 9 years of age and older and for males between 9 and 26 years of age, since 2007 and 2012, respectively. To outline the evidence on a two-dose HPV vaccine schedule and to make recommendations for the optimal HPV immunization schedule in Canada. NACI reviewed the evidence used by the World Health Organization's (WHO's) Strategic Advisory Group of Experts (SAGE) on Immunization for the two-dose HPV immunization schedule recommended for immunocompetent girls 9 to 14 years of age and conducted an additional review of literature for studies not included in, or published after, the SAGE review. A knowledge synthesis was performed then NACI approved specific recommendations and elucidated the rationale and relevant considerations. Based on the evidence available to date, a two-dose HPV immunization schedule among immunocompetent 9- to 14-year-olds is expected to provide similar protective efficacy compared to a three-dose schedule in immunocompetent individuals aged 9 to 26 years. While all studies reviewed included only females, there is no reason to believe that the data would be different in males, given that data from three-dose trials demonstrates similar immune responses. Administration of two doses of HPV vaccine rather than three may increase acceptability by students, parents and health care professionals alike, and may lead to improved HPV immunization coverage and efficiencies by public health agencies. The duration of protection of either two doses or three doses of HPV vaccine is not yet known; research is encouraged to determine whether there is need for a booster dose. Based on the evidence available to date, a two-dose HPV immunization schedule (given at least six months apart) among immunocompetent 9- to 14-year-olds may be considered by individuals and jurisdictions to allow for potential cost savings and other individual and programmatic advantages. A three-dose schedule should be used in individuals 15 years of age and older, as well as immunocompromised individuals and immunocompetent HIV-infected individuals. The new and complete set of current recommendations for HPV vaccines will be published in the updated HPV chapter in the Canadian Immunization Guide in the near future.

Examining Provincial HPV Vaccination Schemes in Canada: Should We Standardise the Grade of Vaccination or the Number of Doses?

Human papillomavirus (HPV) infection is the most common sexually transmitted infection, which is linked to several cancers and genital warts. Depending on the Canadian province, the quadrivalent vaccine is given to girls in grades 4 through 10 with either a two- or three-dose schedule. We use a mathematical model to address the following research questions: (1) Does the grade at which the girls are vaccinated significantly affect the outcome of the program? (2) What coverage rate must the provinces reach in order to reduce the impact of HPV on the Canadian population? (3) What are the implications of vaccinating with two versus three doses? The model suggests the grade of vaccination and the number of doses do not make a significant difference to the outcome of the public vaccination program. The most significant factor is the coverage rate of children and adults. We recommend that provinces vaccinate as early as possible to avoid vaccine failure due to previous infection. We also recommend that the main focus of the program should be on obtaining a large enough coverage rate for children and/or adults in order to achieve the desired outcome with either two or three doses of the vaccine.

Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial

Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood. We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232. Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C. Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study. This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.

Immunogenicity of hepatitis B vaccine in patients with inflammatory bowel disease and the benefits of revaccination.

The vaccination against hepatitis B virus (HBV) is recommended in patients with inflammatory bowel disease (IBD). However, the response to this vaccine seems to be lower in IBD patients than in the general population. This study aims to evaluate the immunogenicity of the HBV vaccine in a cohort of patients with IBD, to associate factors with the response and to analyze the effects of a second schedule vaccination. We conducted a retrospective cohort study of adults with IBD, susceptible to HBV infection. All patients received a three-dose standard schedule of HBV vaccine. Non-responders were revaccinated with a second three-dose standard schedule. Adequate immunity to HBV was defined as antibodies against hepatitis B surface antigen (anti-HBs) ≥ 10 mIU/mL. Age, comorbidities, treatment, and other variables were collected. One hundred seventy-two patients were included and received the first HBV vaccine schedule. Eighty-seven developed anti-HBs ≥ 10 mIU/mL (50.6%; 95% confidence interval [CI]: 42.9-58.3). From the non-responders, 53 were revaccinated and 28 showed an adequate serological response (52.8%; 95% CI: 38.6-66.7). Age older than 55 years (OR: 3.6; 95% CI: 1.3-10.2) and comorbidities (OR: 2.8; 95% CI: 1.1-7.1) were associated with suboptimal response. In the multivariate analysis, only age was a predictor of non-response (age higher than 55 years; OR: 3.9; 95% CI: 1.3-11.9) CONCLUSION: The response rate to the HBV vaccine is lower in patients with IBD compared with the general population, especially in those older than 55 years. Revaccination improved response rate by 50%.

Effects of Vaccination on Invasive Pneumococcal Disease in South Africa

BackgroundIn South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease.MethodsWe conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups.ResultsSurveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (−89%; 95% confidence interval [CI], −92 to −86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, −63 to −50), from 3.7 to 1.6 cases per 100,000 person-years.ConclusionsRates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.)

An Update of Cost-Effectiveness of Rotavirus Vaccination in Indonesia: Taking a Birth-Dose Vaccination Strategy into Account.

Objectives: Rotavirus infection was reported as the major cause of severe diarrhea in children under 5-years-old in Indonesia. A low cost rotavirus vaccine to protect infants from birth has been developed for developing countries, such as Indonesia. This study aims to update our initial analysis on the cost-effectiveness of rotavirus vaccination in Indonesia, taking a birth-dose vaccination strategy explicitly into account. Methods: An age-structured cohort model was developed for the 2013 Indonesia birth cohort. Applying different rotavirus vaccine efficacies for formula-fed and breastfed infants, we compared two vaccination strategies: (i) three-dose schedule at 2, 3 and 4 months of age, and (ii) three-dose schedule at 0, 1, and 2 months of age. We applied a 5-year-time-horizon with 1 monthly analytical cycles for children less than 1 year of age and annually thereafter. Also, we used Monte Carlo simulations to examine the economic acceptability and affordability of the rotavirus vaccination. Results: Rotavirus vaccination would reduce rotavirus-diarrhea cases in children under 5-years-old by 475,806 and 489,259 cases for the first and second strategies, respectively. Considering amarket price of US$ 5 per dose, the Indonesian government would require budgets of US$ 65.0 million and US$ 65.3 million for the first and second strategies, respectively.The incremental cost-effectiveness ratios wereUS$ 150 and US$ 146for the first and second strategies, respectively, which were much lower than the 2013 Indonesian Gross Domestic Product (GDP) per capita of US$ 4,790. Conclusions: The implementation of a birth-dose rotavirusvaccination strategy in Indonesia would be more cost-effective than a later vaccination schedule. The mortality rate and vaccine price were the most influential parameters impacting the costeffectiveness results.

Comparing the cost-effectiveness of two- and three-dose schedules of human papillomavirus vaccination: A transmission-dynamic modelling study

BackgroundRecent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada. MethodsWe used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost. FindingsAssuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between $7900–24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated. InterpretationTwo-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls.

Development of a reverse genetics system for respiratory syncytial virus long strain and an immunogenicity study of the recombinant virus.

BackgroundRespiratory Syncytial Virus (RSV) is an important human respiratory pathogen, particularly of infants and older adults, and despite several decades of research and development, no licensed vaccine is available. Studies have confirmed that enhancement of RSV disease does not occur after inoculation with RSV live-attenuated vaccine candidates, making such vaccines preferable. In this paper, reverse genetics was used to construct two recombinant viruses, a recombinant Long strain (rLong) and rLong-∆G-EGFP; rLong-∆G-EGFP is a recombinant mutant in which G was replaced with the EGFP gene, based on the Long strain of RSV.ResultsBoth rLong and rLong-∆G-EGFP were constructed successfully and recovered in Hep-2 cells, and autofluorescence was observed in rLong-∆G-EGFP-infected cells during consecutive passages. Titers of rLong and rLong-∆G-EGFP were ~100-fold lower than the parental strain. Although virulence was attenuated, high titers of neutralizing antibodies were induced in BALB/c mice after being inoculated with recombinant viruses in a three-dose schedule. Unexpectedly, the neutralizing antibody titer in rLong-∆G-EGFP-immunized recipients did not decline significantly compared with the rLong strain. Protective efficacy of recombinant viruses in lung tissue was up to 100%, and the serum neutralizing antibody levels could stabilize at 21 days with no significant fall post-challenge. Enzyme-linked immunospot (ELISPOT) assays showed that both recombinant viruses were capable of inducing CD8+ T cell immune responses, which are crucial for virus clearance, and that rLong stimulated a higher level of IFN-γ production by comparison. In terms of inducing a balanced immune response, rLong-∆G-EGFP elicited slightly higher levels of IgG2a antibodies and lower levels of IgG1/IgG2a than the rLong virus.ConclusionsThis study suggested that immunization with rLong and rLong-∆G-EGFP were immunogenic and protected against RSV infection in the lower respiratory tract of BALB/c mice better than in the nose. Because of a relative low IgG1/IgG2a ratio, rLong-∆G-EGFP was more inclined to make CD4+ T cells, shifting toward a Th1-type response, indicating that the generation of a more balanced Th1/Th2 response was desirable. This explorative study on the recombinant Long viruses also contributed to obtaining more RSV attenuated candidates by a reverse genetics approach.

ACIP assesses pneumococcal vaccine, HPV, and more

Addressing areas of concern in the vaccine world was the focus of the June 25–26 meeting of CDC’s Advisory Committee on Immunization Practice (ACIP). As APhA’s representative to ACIP, I prepared this highlights summary for Pharmacy Today. More in-depth notes from the pharmacist’s perspective are online in the Immunization Center on pharmacist.com , and complete minutes of the meeting will be published on CDC’s website (www.cdc.gov/vaccines/acip/). In addition, three topics presented at June’s meeting on influenza vaccines, meningococcal vaccine, and vaccinations in immunocompromised patients are covered as separate articles in this issue’s Special Immunization Section on pages 42–46. As mentioned at the February ACIP meeting, a three-dose, 13-valent pneumococcal conjugate vaccine (Prevnar 13 [PCV13]—Pfizer) schedule is used in many other countries, whereas the United States currently has a fourdose schedule. The ACIP working group was tasked with re-evaluating the current U.S. schedule. CDC has been monitoring invasive pneumococcal disease and evaluating serotypes that have caused disease. The serotypes in the 7-valent pneumococcal conjugate vaccine (Prevnar 7 [PCV7]—Wyeth) have virtually disappeared, and the serotypes in PCV13 vaccine are rapidly disappearing. A Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis for reducing the number of doses of PCV13 in the pediatric schedule demonstrated limited evidence for three versus four doses. The working group noted that it was still not ready to make a recommendation for change but will continue its evaluation. The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) results were also presented. Although FDA licensed PCV13 for adults older than 50 years, ACIP has not recommended this use. CAPiTA was a randomized, controlled trial of PCV13 compared with placebo in 84,496 patients older than 65 years. The primary study tested the efficacy of PCV13 in preventing vaccine-serotype pneumococcal community-acquired pneumonia (CAP). The trial reported a 46% reduction in CAP, with 49 cases in the vaccine group compared with 90 cases in the placebo group. The ACIP working group was tasked with considering if PCV13 should be administered routinely to all adults aged 65 years or older. Members estimated that the number needed to treat to prevent a single case of PCV13-type invasive pneumococcal disease was 20,400; 1,620 for inpatient CAP; and 1,110 for outpatient CAP. The GRADE analysis supported the use of PCV13 in adults; however, herd immunity may limit the need for PCV13 in the future. Thus, ACIP concluded that a shortterm recommendation may be warranted. Since a timely decision is needed for the 2014–15 respiratory season, the committee may meet over the summer to discuss the issue further. Clinical data on the new 9-valent human papillomavirus (HPV) vaccine by Merck were presented, continuing the presentation introduced at February’s meeting. The 9-valent HPV vaccine has proven to be very effective (97%) in reducting disease caused by the new HPV serotypes and noninferior to the serotypes in the original vaccine. In addition, the safety profile appears to be similar to that of the original vaccine, with local reactions the most common adverse effects. Based on these studies, the 9-valent HPV vaccine will be licensed for girls and women aged 9 years to 26 years and for boys aged 9 years to 15 years. Studies have been performed evaluating a two-dose schedule, and the ACIP working group is evaluating whether decreasing to two doses from the current three doses should be considered. Extending the interval between the doses may also be an important issue, and several ongoing trials are evaluating this factor. The ACIP working group plans to evaluate the 9-valent HPV vaccine and compare a twoversus three-dose schedule. While several yellow fever vaccines are used around the world, YF-Vax (Sanofi Pasteur) is approved for use in the United States. The vaccine is recommended for persons aged 9 months or older who are traveling or living in areas at risk. It is given in a single subcutaneous dose at intervals of 10 years. Many contraindications and precautions exist, and careful screening must be performed. Reviews of the literature show that 90% of vaccine recipients have high antibodies at 10 to 20 years. High titers have been detected as long as 60 years postvaccination, and very few vaccine failures have been reported. In April 2013, the Strategic Advisory Group of Experts for the World Health Organization recommended eliminating the yellow fever vaccine booster. A GRADE analysis was applied by the ACIP working group; however, very few data are available. The working group recommended that booster doses no longer be administered to most travelers or laboratory workers. After discussion by several experts opposed to the recommendation because of limited data, ACIP postponed a vote until it reconvenes October 29–30.

HPV vaccination in women aged 27 to 45years: what do general practitioners think?

BackgroundAlthough the Human Papillomavirus (HPV) vaccine is registered in Australia for females aged 9 to 45 years, females aged 27 to 45 years have shown limited vaccine uptake. Our study explored general practitioners’ (GPs) views concerning HPV vaccination of females in this age group, with particular focus on the barriers and the facilitators to the delivery of the HPV vaccine.MethodsSemi-structured telephone interviews were conducted with 24 randomly selected general practitioners from metropolitan Melbourne. Questions were based on a theoretical framework that explained the barriers and facilitators to professional behaviour change.ResultsAccording to the GPs, the major barriers to the uptake of the HPV vaccine included the cost of the vaccine, time constraints, and the three-dose schedule. Other barriers that were identified included GPs’ and patients’ beliefs that females in this age group were at low risk of contracting HPV, lack of awareness about the vaccine, and uncertainty about the benefits of this vaccine for females in this age group. In contrast, the facilitators that were identified included the availability of the vaccine on site, the availability of vaccine clinics or nurses for administering the vaccine, the availability of information related to the vaccine either on site or online, and positive opinions from experts in the field.ConclusionsOur study has identified some of the barriers and facilitators to the delivery and uptake of the HPV vaccine in females aged 27 to 45 years, as perceived by GPs. Further studies should be conducted to determine which of these should be targeted or prioritised for intervention. The views of women in this age group should also be considered as these would also be influential in designing effective intervention strategies for improving the delivery and uptake of the HPV vaccine.

Immunogenicity of quadrivalent HPV and combined hepatitis A and B vaccine when co-administered or administered one month apart to 9–10 year-old girls according to 0–6 month schedule

Background. No immunogenicity data has been reported after a single dose of the quadrivalent HPV vaccine (qHPV-Gardasil®) and no data are available on co-administration of this vaccine with the HAV/HBV vaccine (Twinrix-Junior®). Two pre-licensure studies reported similar anti-HPV but lower anti-HBs titers when co-administering HPV and HBV vaccines. Objectives. To assess the immunogenicity of the qHPV and HAV/HBV vaccine when co-administered (Group-Co-adm) or given one month apart (Group-Sep) and to measure the persistence of HPV antibodies three years post-second dose of qHPV vaccine in both study groups. Methods. 416 9–10 year-old girls were enrolled. Vaccination schedule was 0–6 months. Anti-HAV and anti-HBs were measured in all subjects 6 months post-first dose and 1 month post-second dose. Anti-HPV were measured 6 months post-first dose in Group-Co-adm and in all subjects 1 and 36 months post-second dose. Results. Six months post-first dose: 100% of subjects had detectable anti-HAV and 56% and 73% had detectable anti-HBs in Group-Co-Adm and Group-Sep, respectively. In Group-Co-adm 94, 100, 99 and 96% had detectable antibodies to HPV 6, 11, 16 and 18, respectively. One month post-second dose of qHPV and HAV/HBV vaccine, in both study groups 99.5–100% of subjects had an anti-HAV titer ≥ 20IU/L, 97.5–97.6% an anti-HBs level ≥ 10IU/L, and 100% had an anti-HPV titer ≥ 3LU. Thirty-six months post-second dose of qHPV all but four subjects (99%) had antibodies to HPV18 and 100% had antibodies to HPV6, 11 and 16. The great majority (97–100%) had an anti-HPV titer ≥ 3 LU. Post-second dose administration of qHPV and HAV/HBV, no meaningful difference was observed in the immune response in the two study groups to any component of vaccines. Conclusions. The results indicate that qHPV and HAV/HBV can be given during the same vaccination session. Two doses of of qHPV and HAV/HBV vaccines induce a strong immune response. Three years post-second dose of qHPV, the great majority of subjects had antibodies to HPV types included in the vaccine. A two-dose schedule for pre-adolescents might be a reasonable alternative to the currently approved three-dose schedules.

Antibody avidity measurements in recipients of Cervarix® vaccine following a two-dose schedule or a three-dose schedule

The HPV-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer and contains recombinant virus-like particles (VLPs) assembled from the L1 major capsid proteins of human papillomavirus (HPV) strains 16 and 18. Although a correlate of protection has yet to be identified, HPV-specific antibodies are thought to prevent virus infection of the genital mucosa. Therefore, antigen-specific antibodies as assessed by ELISA or pseudovirion-based neutralisation assay are frequently measured in clinical trials to substantiate the immune responses induced by the vaccine. Measuring antigen-antibody binding avidities, which reflects the degree of affinity maturation in the B-cells, is another valuable method to assess the quality of the antibody responses. Here we describe the antigen-specific antibody avidities in samples taken from a clinical trial examining the feasibility of adopting a two-dose (Months 0 and 6) schedule for 9–14 year olds instead of the three-dose schedule (Months 0, 1 and 6). Antibody avidity (i.e. avidity index [AI]) was determined in the ELISA by the ratio of antibody concentrations in serum samples treated or not with the chaotropic agent NaSCN. Importantly, in the comparison between the groups of two-dose and three-dose recipients, no differences in AIs were observed at Months 7, 24 and 48. The results suggest that from Month 7 to 48, the quality of the antibody response in terms of avidity was similar in the two-dose recipients to that in the three-dose recipients. Hence these results support the adoption of a two-dose schedule in 9–14 year-old girls.

Immune response to hepatitis B vaccine with high antigen content in non-responders after standard primary vaccination in Chinese adults

ContextAlternative schedules are needed to provide greater immunogenicity in adults who fail to respond to the standard hepatitis B (HB) vaccine regimen. ObjectiveTo evaluate the immunogenicity and safety of high antigen content HB vaccine formulations administered to non-responders after routine primary vaccination. Design setting, and participantsThis was a phase III, double-blind, controlled clinical trial in China. We enrolled healthy participants (16–60 years old) seronegative for HB surface (HBs) antigen after primary vaccination, who had HBs antibody (anti-HBs) titres <10mIU/ml at 28 days following routine vaccination with licensed HB vaccine containing 10μg of antigen. Participants were randomised (2:2:1) to receive three booster doses of HB vaccine formulations containing 60μg, 30μg or 10μg of antigen per dose 28 days apart. Blood samples were obtained pre-vaccination and 28 days after each dose to assess immunogenicity. Reactogenicity and safety were evaluated up to 28 days after each vaccine dose. ResultsSeroconversion rates were ≥92.1% and ≥87.1% as from the second dose of the 60μg and 30μg HB vaccine formulations, respectively, with geometric mean concentrations (GMCs) of ≥286.0mIU/ml and ≥164.0mIU/ml. In the 10μg HB vaccine group the seroconversion rates were ≥83.0% and the GMCs ≥110.1mIU/ml as from the second vaccine dose. All HB vaccine formulations were well tolerated: 352/1091 (32.3%) participants reported at least one injection-site or systemic adverse reaction (145/434 [33.4%] from the 60μg group; 138/435 [31.7%] from the 30μg group and 69/222 [31.1%] from the 10μg group). Most reactions were mild or moderate and resolved within 24h. No serious adverse events were reported. ConclusionBooster vaccination with a three-dose schedule of a high antigen content HB vaccine formulation was immunogenic and well tolerated in healthy adults. Clinicaltrials.gov identifierNCT01203319.

Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine (Cervarix®): A Guide to Its Two-Dose Schedule in Girls Aged 9–14 Years in the EU

A two-dose vaccination schedule for the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is approved for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in girls aged 9-14 years in countries in the EU and elsewhere. In this patient population, the two-dose schedule elicited a high immunogenic response that matched that of the three-dose schedule in women aged 15-25 years and, therefore, was inferred to provide clinical protection against oncogenic HPV cervical infection and, consequently, against precancerous lesions and cervical cancer.

HPV vaccines to prevent cervical cancer and genital warts: an update

Cervical cancer is an important public health problem worldwide, and especially in developing countries. The link between cervical cancer and oncogenic human papillomavirus (HPV) infection has been clearly established. Furthermore, non-oncogenic HPV are responsible for the majority of genital warts. Two prophylactic HPV vaccines are available, which have the potential of considerably reducing HPV-related morbidity and mortality. Both vaccines are based on virus-like particles of the L1 capsid protein, and are highly efficacious and immunogenic if given before exposure to HPV, i.e. to adolescent girls between 9 and 13 years of age in a three-dose schedule. This review describes the immunology of natural HPV infections and the immune response evoked through vaccination. The current duration of protection is 8.4 years with the bivalent vaccine (HPV16/18) and 5 years with the quadrivalent vaccine (HPV6/11/16/18). Research is on-going to evaluate the efficacy of the current vaccines in a two-dose schedule, as compared to the recommended three-dose schedule. To increase the protection, the development and testing of a nine-valent prophylactic HPV vaccine (HPV6/11/16/18/31/33/45/52/58) is being undertaken. Research is also directed towards therapeutic vaccines and the development of a prophylactic L2 vaccine.

Phyllanthus for chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a common disease worldwide. In 2011, CDC received 39,636 reports of chronic HBV infection, with many additional people likely unaware of their disease due to its asymptomatic nature.1.www.cdc.gov/hepatitisStatistics/2011Surveillance/Commentary.htm.Google Scholar The three-dose schedule HBV vaccine is 95% effective in preventing HBV infection and provides immunity for at least 20 years. Many supplements such as milk thistle are used for liver disease treatment. Lesser known plants such as Phyllanthus species are used for hepatic disorders as part of traditional Chinese medicine. In vitro studies reported that Phyllanthus species contain lignans possessing cytotoxic activity, which suppresses HBV antigen secretion. Two systematic reviews have evaluated Phyllanthus in HBV treatment. A 2001 review of Phyllanthus treatment in 22 randomized trials reported that the plant may be beneficial in clearing HBV markers.2.J Viral Hepatitis. 2001; 8: 358-366Crossref PubMed Scopus (75) Google Scholar In addition, liver function tests were normalized without serious adverse effects from the plant. The studies used extracts of the whole plant Phyllanthus; only one trial indicated the specific plant species used (P. urinaris). Trials used multiple dosage forms: Phyllanthus granules were either extracted and encapsulated as an oral tablet or used to create a decoction as a tea. Studies had small sample sizes and a limited description of randomization and allocation procedures. This introduces bias and questionable statistical power, leading to questions about the significance of the findings. The Jadad scale was used to assess study quality, and only five were ranked high quality.Evidence has suggested a potential benefit of Phyllanthus extracts when used with antiviral therapy A 2010 systematic review of the effectiveness of Phyllanthus species in chronic HBV infection evaluated data on 1,326 patients of varying ages in 16 different trials.3.Cochrane Database Syst Rev. 2011 doi:10.1002/14651858.CD008960.pub2.Google Scholar Trials used multiple species—P. amarus, P. urinaria (Chamber bitter), and P. niruri—and preparations prepared in the same manner as in the 2001 review. This systematic review used data collection and analysis methodology based on the Cochrane Handbook of Systematic Reviews of Interventions. Fifteen trials compared Phyllanthus in combination with standard antiviral treatment versus standard antiviral therapy alone. Phyllanthus significantly reduced serum HBV DNA (a marker of efficacy) as well as HBeAg (a marker of viral replication) when combined with antiviral therapy. The summary concluded that based on current evidence, Phyllanthus may be beneficial when combined with standard antiviral therapy but has no benefit alone. Most trials in the 2010 review are at high risk for bias due to methods of allocation and blinding, incomplete outcome data, selective outcome reporting, and other factors. The duration of follow-up after treatment was a major limitation. One trial measured outcomes for 2 weeks, another for 24 weeks, and another for 2 years. Available studies did not provide data on the effect of Phyllanthus on morbidity and mortality. Fewer than 2% of participants experienced adverse events, which included light nausea, decreased appetite, and stomachache.HIGHLIGHTS■HBV infection is best prevented by avoiding shared needles and unsafe sexual practices, in addition to being vaccinated against HBV.■In vitro studies reported that Phyllanthus species contain lignans possessing cytotoxic activity, which suppresses HBV antigen secretion. ■HBV infection is best prevented by avoiding shared needles and unsafe sexual practices, in addition to being vaccinated against HBV.■In vitro studies reported that Phyllanthus species contain lignans possessing cytotoxic activity, which suppresses HBV antigen secretion. Chronic HBV infection is a serious condition that may result in liver cancer or cirrhosis. HBV infection is best prevented by avoiding shared needles and unsafe sexual practices, in addition to being vaccinated against HBV. Dietary supplements are not a replacement for maintaining good liver health practices, including moderation of alcohol use. Phyllanthus species have been promoted for their potential liver benefits. Evidence has suggested a potential benefit of Phyllanthus extracts when used with antiviral therapy. Extracts may contain different species in varied strengths. Most Phyllanthus supplements recommend one capsule with a meal two to three times daily. As always, patients should purchase supplements from reputable sources.

Overcoming barriers to HPV vaccination: Non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose schedule at 21 months

For middle and low-income countries, the cost of HPV vaccines remains challenging. We conducted an open-label nonrandomized clinical trial evaluating immune response to the HPV–16/18 AS04-adjuvanted vaccine administered on a standard (months (M) 0–1–6) versus extended schedule (M 0–6–60) at 7, 21, 60, 72 and 120 months post-vaccination. Participants were females recruited in Morelos, Mexico: 474 girls aged 9–10 years and 500 women aged 18–24 years receiving a standard schedule, and 1026 girls aged 9–10 years receiving an extended schedule (currently the girls in the extended schedule had received only the first 2 doses). This report presents the interim analysis results for non-inferiority between the regimes conducted with the current available data at 21 months after the first dose, with serum antibodies assessed by ELISA. A pre-stated margin of non-inferiority was defined by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI]≤2.0) between the standard and the two-dose schedule in girls at month 21. Immune response to the vaccine was strongest in adolescent girls and in the 3-dose group. Statistical non-inferiority of the two-dose versus three-dose groups was demonstrated. At 21 months, comparing the adolescent 2-dose versus 3-dose groups, the GMT ratio and 95% CI were 1.66 (1.55–1.81) and 1.67 (1.51–1.86) for HPV16 and 18, respectively. The two-dose regimen was non-inferior when compared to the three-dose response in same-age girls and with women aged 18–24 years after 21 months of follow-up. The reduction in the number of doses from the current three-dose schedule may lower overall costs associated with the vaccination and increase accessibility and compliance with the recommended dosing of the HPV vaccine.

ACIP tackles range of vaccine topics at meeting

The following article is part one of a two-part series covering vaccine topics addressed at the October 2013 meeting of the Advisory Committee on Immunization Practice (ACIP). More topics will be covered in next month's Immunization Update. The recent publication of the 2013–14 ACIP influenza recommendations included new vaccine strains, licensure of six new influenza vaccines, and clarification of egg allergies. Since the publication of the report, Flulaval Quadrivalent (ID Biomedical) was licensed and Flulaval Trivalent was approved for a new age indication (patients >3 years). As of October 12, influenza activity was low, which is normal for this early in the influenza season. About 90% of the strains reported so far are type A. Influenza-like illness (ILI) activity remains low. Vaccination coverage rates for the 2012–13 season were reviewed. A total of 134.9 million doses were distributed last season, with coverage rates of 57% in children, 41.5% in adults older than 18 years, and 66% in individuals 65 years or older. Rates were higher in all age groups. A summary of the Fluzone HighDose (Sanofi Pasteur) vaccine efficacy trial results was presented. The prelicensure trials demonstrated that the vaccine induced a statistically significantly higher antibody response against all three strains compared with regulardose Fluzone vaccine. Fluzone HighDose is indicated for adults 65 years or older, while regular-dose Fluzone is recommended for patients 6 months or older. A study comparing the clinical efficacy of Fluzone High-Dose with Fluzone trivalent vaccine was presented. The study enrolled approximately 32,000 participants 65 years or older in 128 study sites over two influenza seasons. The study was designed to compare the efficacy with respect to laboratory-confirmed influenza caused by any influenza strain with the occurrence of protocol-defined ILI. Relative efficacy was 24.2% higher for Fluzone High-Dose (1.43% vs. 1.89% ILI). Slight improvement also was seen for pneumonia, hospitalizations, and cardiorespiratory episodes. Additional analysis and studies are under way.■ACIP's 2013–14 influenza recommendations include new vaccine strains, licensure of six new influenza vaccines, and clarification of egg allergies.■ACIP needs more evidence before it can recommend reducing the number of doses in the pneumococcal childhood series from three to four doses. ■ACIP's 2013–14 influenza recommendations include new vaccine strains, licensure of six new influenza vaccines, and clarification of egg allergies.■ACIP needs more evidence before it can recommend reducing the number of doses in the pneumococcal childhood series from three to four doses. Three conjugated meningococcal vaccines have been approved in the United States. MenACYW-135-CRM (Menveo—Novartis) recently received an indication for age as early as 2 months (2 months to 55 years). The studies submitted for FDA approval were presented. The vaccine demonstrated effective blood titers and did not interfere with other vaccines given in the infant series. The GRADE analysis was similar to the other meningococcal vaccines. The working group decided that Menveo should be added as an option for vaccinating high-risk infants. Many countries have implemented pneumococcal conjugate vaccine (PVC) in a three-dose schedule (compared with the four-dose schedule in the United States). CDC has been evaluating the incidence of invasive pneumococcal dis-ease (IPD) in children since 2010 (when 13-valent PCV [PCV13] was licensed) and is observing a decline. Also, as a result of herd effect, IPD appears to be declining in adults. The vaccine effectiveness in one study against all IPD in children was 65%. However, if vaccine effectiveness is measured against the PCV13 serotypes in the vaccine, it climbs to 89%. Because the World Health Organization recognizes a three-dose schedule as acceptable, the working group is discussing a reduction in the number of doses in the pneumococcal childhood series. We also are seeing a large decline in disease burden in the United States caused by serotypes in the vaccine. Looking at studies from other countries, the vaccine effectiveness ranged from 70% to 100% against vaccine-type IPD. The vaccines used in these studies included PCV7, −9, and −13. The four-dose series studies reported a vaccine effectiveness of 81% to 100%. No studies comparing three- and four-dose schedules have emerged. Differing types of studies (e.g., randomized controlled versus observational) and differing diseases (e.g., IPD, pneumonia, acute otitis media) are under way. In conclusion, the three-dose PCV studies demonstrated effectiveness against IPD, pneumonia, and otitis media. The immunogenicity studies demonstrated that after the primary series, three doses are more effective than two, but this difference does not continue after the second year of life. Also, little difference was noted after the booster dose for the two-plus-one versus three-plus-one series. The same pattern was seen with nasopharyngeal carriage. However, the differences may not be meaningful because PCV7 serotypes rarely cause disease and the PVC13 serotype disease is disappearing. The herd effects are similar, so changes at the population level are not expected.

Safety of Human Papillomavirus Vaccines: A Review

Vaccination to prevent human papillomavirus (HPV)-related infection leading to cancer, particularly cervical cancer, is a major public health breakthrough. There are currently two licensed HPV vaccines, both of which contain recombinant virus-like particles of HPV types 16 and 18 (which account for approximately 70 % of cervical cancer). One vaccine also protects against HPV types 6 and 11, which cause genital warts. The safety profile of both vaccines was assessed extensively in randomised controlled clinical trials conducted prior to licensure and has been further elucidated following licensure from surveillance and specific studies in large populations. This review aims to examine current evidence regarding the safety of HPV vaccines. In summary, both vaccines are associated with relatively high rates of injection site reactions, particularly pain, but this is usually of short duration and resolves spontaneously. Systemic reactions have generally been mild and self-limited. Post vaccination syncope has occurred, but can be avoided with appropriate care. Serious vaccine-attributable adverse events, such as anaphylaxis, are rare, and although not recommended for use in pregnancy, abnormal pregnancy outcomes following inadvertent administration do not appear to be associated with vaccination. HPV vaccines are used in a three-dose schedule predominantly in adolescent females: as such case reports linking vaccination with a range of new onset chronic conditions, including autoimmune diseases, have been made. However, well-conducted population-based studies show no association between HPV vaccine and a range of such conditions. Whilst this reassuring safety profile affirms the positive risk benefit of vaccination, as HPV vaccine use expands into more diverse populations, including males, ongoing safety assessment using well-conducted studies is appropriate.

Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children

BackgroundHepatitis A is mostly a self-limiting disease but causes substantial economic burden. Consequently, United States Advisory Committee for Immunization Practices recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults. The hepatitis A vaccine is highly effective but the duration of protection is unknown. MethodsWe examined the proportion of children with protective hepatitis A antibody levels (anti-HAV ≥20mIU/mL) as well as the geometric mean concentration (GMC) of anti-HAV in a cross sectional convenience sample of individuals aged 12–24 years, who had been vaccinated with a two-dose schedule in childhood, with the initial dose at least 5 years ago. We compared a subset of data from persons vaccinated with two-doses (720 EL.U.) at age 3–6 years with a demographically similar prospective cohort that received a three-dose (360 EL.U.) schedule and have been followed for 17 years. ResultsNo significant differences were observed when comparing GMC between the two cohorts at 10 (P=0.467), 12 (P=0.496), and 14 (P=0.175) years post-immunization. For the three-dose cohort, protective antibody levels remain for 17 years and have leveled-off over the past 7 years. ConclusionThe two- and three-dose schedules provide similar protection >14 years after vaccination, indicating a booster dose is not needed at this time. Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term.