Effectiveness of a universal vaccination program with an HPV quadrivalent vaccine in young Brazilian women

We examined human papillomavirus (HPV) vaccine effectiveness in a nationwide sample of women aged 16 to 25 years who utilized the public health system in Brazil. This was a cross-sectional, multicentric survey conducted between September 2016 and November 2017 (POP-Brazil Study). A total of 5,945 young adult women were recruited from 119 public primary care units from all 27 federative units of Brazil by trained health professionals. The participants participated in a face-to-face interview and provided biological samples for genital HPV analysis. HPV genotyping was performed using a Linear Array HPV genotyping test in a central laboratory. Sampling weights were applied to the data. Overall, 11.92% (95% CI 10.65, 13.20) of the participants reported having been vaccinated. The frequency of vaccination was highest in 16- to 17-year-old women, with a decreasing vaccination rate with increasing age, and vaccinated women were more likely to belong to the high socioeconomic status group. The use of a quadrivalent vaccine decreased the HPV types 6, 11, 16, and 18 by 56.78%, from 15.64% in unvaccinated women to 6.76% in vaccinated women (P < 0.01), even after adjustment for age. Those who received the vaccine had lower HPV 16 (2.34% in vaccinated vs 8.91% in unvaccinated, P < 0.01) and 6 rates (2.06% vs 5.77%, P < 0.01). Additionally, a higher rate of high-risk HPV types other than HPV 16 and 18 (40.47% in vaccinated vs 32.63% in unvaccinated, P < 0.01) was observed. In conclusion, the results of this study support the effectiveness of HPV vaccination in Brazil. Continuous surveillance must be assured to monitor the HPV infection rate in the vaccination era.     

Immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study

BackgroundSeqirus 2010 Southern Hemisphere split-virion trivalent inactivated influenza vaccine (IIV3) was associated with increased febrile reactions in children. Studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. We assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4; produced using higher concentration of splitting agent) versus a United States-licensed comparator IIV4 in healthy children aged 5–17 years.MethodsParticipants (N = 2278) were randomized 3:1 and stratified by age (5–8 years; 9–17 years) to receive IIV4 (n = 1709) or comparator IIV4 (n = 569). Primary objective was to demonstrate noninferiority of IIV4 versus comparator IIV4 as assessed by hemagglutination inhibition (HI) geometric mean titer (GMT) ratio (upper bound of two-sided 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper bound of two-sided 95% CI ≤ 10%) for all four vaccine strains. HI antibody titers were assessed at baseline and 28 days postvaccination. Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively.ResultsIIV4 met immunogenicity criteria for noninferiority. Adjusted GMT ratios (comparator IIV4/IIV4) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.01 (95% CI; 0.93, 1.09), 1.05 (0.96, 1.15), 0.89 (0.81, 0.98), and 0.92 (0.83, 1.02), respectively. Corresponding values for differences (95% CI) in seroconversion rates (comparator IIV4 minus IIV4) were −3.1 (−8.0, 1.8), 0.4 (−4.5, 5.3), −3.4 (−8.3, 1.5), and −2.0 (−6.9, 2.9). Fever rates were numerically higher, but not statistically different, with IIV4 versus comparator IIV4. No new safety signals were reported.ConclusionIIV4 demonstrated immunological noninferiority to the comparator IIV4 with a clinically acceptable safety profile in children aged 5–17 years. Increased levels of virus splitting agent seem to have reduced fever rates observed in children with Seqirus IIV3, particularly those aged 5–8 years.Funding: Seqirus Pty Ltd; Clinicaltrials.gov identifier: NCT02545543.     

Efficacy,immunogenicity, and safety of a quadrivalent inactivated influenza vaccine in children aged 6–35 months: A multi-season randomised placebo-controlled trial in the Northern and Southern Hemispheres

Background

A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra?, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged?≥?3?years. This study examined the efficacy and safety of IIV4 in children aged 6–35?months.

Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults

Human papillomavirus (HPV) infection is highly prevalent and can lead to cancer; the development of safe and efficacious vaccines for HPV is a major public health concern. The two licensed HPV vaccines contain recombinant virus-like particles of HPV 16 and 18; one of such vaccines also protects against HPV types 6 and 11 which cause genital warts. We determined safety and immunogenicity of quadrivalent HPV vaccine in HIV-infected and HIV-negative adolescents and young adults, aged 13–27 years. The seroconversion rate, assessed by antibody titers, 1 month after the administration of the third vaccine dose was 0.85 (95% CI 0.75–0.95) in the HIV-infected group and 0.91 (0.83–0.99) in the HIV-negative subjects (p = 0.52). The vaccine was generally safe and well tolerated; the most common side effect was local pain and the most frequent systemic side effect was headache. This is the first report on response to HPV vaccination in both female and male HIV-infected adolescents and young adults and highlights that this population may benefit from HPV immunoprophylaxis. Further studies are needed to examine the long term efficacy of this vaccine in HIV-infected individuals.     

Safety of a quadrivalent human papillomavirus vaccine in a Phase 3, randomized,double-blind,placebo-controlled clinical trial among Chinese women during 90 months of follow-up

Background

A quadrivalent human papillomavirus (qHPV) vaccine (HPV6/11/16/18) has demonstrated efficacy and acceptable safety in international studies. However, these studies did not include participants from mainland China, which has a substantial burden of HPV-related disease. This is the first safety report with a follow-up period of up to 90?months from a randomized, double-blind, placebo-controlled trial of qHPV vaccine in Chinese women 20–45?years of age.

A prospective cohort study of immunogenicity of quadrivalent human papillomavirus vaccination among Alaska Native Children,Alaska, United States

ObjectiveIn the United States, HPV vaccination is routinely recommended at age 11 or 12 years; the series can be started at age 9. We conducted a cohort study to assess long-term immunogenicity of quadrivalent HPV vaccine (4vHPV) in an American Indian/Alaska Native (AI/AN) Indigenous population.MethodsDuring 2011–2014, we enrolled AI/AN girls and boys aged 9–14 years, who were vaccinated with a 3-dose series of 4vHPV. Serum specimens were collected at five time points: immediately prior to doses 2 and 3, and at one month, one year, and two years after series completion. Antibody testing was performed using a multiplex virus-like-particle-IgG ELISA for 4vHPV types (HPV 6/11/16/18).ResultsAmong 477 children (405 girls/72 boys) completing the 3-dose series, median age at enrollment was 11.2 years. Of the 477, 72 (15%) were tested before dose 2 and 70 (15%) before dose 3. Following series completion, 435 (91%) were tested at one month, 382 (80%) at one year, and 351 (74%) at two years. All tested participants had detectable antibody to 4vHPV types at all time points measured. Geometric mean concentrations (GMCs) for 4vHPV types at one month and two years post-series completion were 269.9 and 32.7 AU/ml for HPV6, 349.3 and 42.9 AU/ml for HPV11, 1240.2 and 168.3 IU/ml HPV16, and 493.2 and 52.2 IU/ml for HPV18. Among children tested after each dose, GMCs after doses 1 and 2 were 3.9 and 32.2 AU/ml for HPV6, 5.3 and 45.6 AU/ml for HPV11, 20.8 and 187.9 IU/ml for HPV16; and 6.6 and 49.7 IU/ml for HPV18. No serious adverse events were reported.ConclusionAll AI/AN children developed antibodies to all 4vHPV types after vaccination. GMCs rose after each dose, then decreased to a plateau over the subsequent two years. This cohort will continue to be followed to determine duration of antibody response.     

Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink

Background

In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009.

Methods

Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis.

Results

A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization).

Conclusions

In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.     

Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 2-10 years of age

Background

Routine administration of quadrivalent meningococcal conjugate vaccine to adolescents and certain high risk groups is recommended in the United States and Canada. We compared the immunogenicity and safety of an investigational quadrivalent meningococcal vaccine conjugated to CRM-197 (MenACWY-CRM) with a licensed quadrivalent vaccine conjugated to diphtheria toxoid (MCV4) in children aged 2–10 years.

Methods

Eligible 2–5-year-olds were randomized 1:2:2 to receive either 2 doses of MenACWY-CRM, or 1 dose of MenACWY-CRM or MCV4; 6–10-year-olds were randomized 1:1 to receive a single dose of MenACWY-CRM or MCV4. The primary immunogenicity assessment was seroresponse separately for the two age cohorts 28 days following a single dose of MenACWY-CRM or MCV4. Noninferiority and superiority criteria were predefined. Solicited injection-site and systemic reactions were collected for the 7 days postvaccination.

Results

A total of 2907 children were randomized to receive study vaccine. MenACWY-CRM met statistical superiority criteria vs. MCV4 for groups W and Y and was noninferior for group C in both age strata. For group A, noninferiority criteria were not met; the group A seroresponse rates for MenACWY-CRM and MCV4, respectively were 72% (95% confidence interval 68–75%) and 77% (73–80%) in 2–5-year-olds and 77% (73–80%) and 83% (79–86%) in 6–10-year-olds. When the two age strata were combined (2–10-year-old children), MenACWY-CRM was noninferior to MCV4 for all four groups, and statistically superior for groups C, W, and Y. Safety parameters were similar across age cohorts and vaccines groups.

Conclusions

MenACWY-CRM and MCV4 were immunogenic and well tolerated in children aged 2–10 years. Seroresponse to MenACWY-CRM was statistically noninferior to MCV4 for all groups, and statistically superior for groups C, W, and Y.

Trial registration

Clinicaltrials.gov identifier: NCT00616421.     

Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized clinical trial

BackgroundA high-dose, split-virion inactivated trivalent influenza vaccine (IIV3-HD; Fluzone® High-Dose, Sanofi Pasteur) is available for adults ≥65 years of age. This study examined the safety and immunogenicity of a quadrivalent high-dose split-virion inactivated influenza vaccine (IIV4-HD).MethodsThis was a randomized, modified double-blind, active-controlled, multi-center trial in healthy adults ≥65 years of age. Subjects were randomized in a 4:1:1 ratio to receive a single intramuscular injection of IIV4-HD, the licensed IIV3-HD, or an IIV3-HD containing the alternate B-lineage strain. Hemagglutination inhibition (HAI), seroneutralisation, and anti-neuraminidase antibody titers were measured at baseline and day 28. Solicited reactions were collected for up to 7 days, unsolicited adverse events up to 28 days, and serious adverse events up to 180 days. The primary immunogenicity objective was to demonstrate that IIV4-HD induces HAI geometric mean titers (GMTs) and seroconversion rates that are non-inferior to those induced by IIV3-HD. Secondary objectives were to describe the safety of IIV4-HD and IIV3-HD and to demonstrate that IIV4-HD induces HAI GMTs and seroconversion rates that are superior to those induced by IIV3-HD not containing the same B-lineage strain.ResultsThe study included 2670 adults ≥65 years of age. For all four strains, HAI GMTs and seroconversion rates induced by IIV4-HD were non-inferior to those induced by IIV3-HDs containing the same strains. For both B strains, HAI GMTs and seroconversion rates induced by IIV4-HD were superior to those induced by IIV3-HD not containing the same B–lineage strain. Seroneutralisation and anti-neuraminidase antibody responses, measured in a subset of subjects, were similar. No new safety concerns were identified, and the safety profiles of IIV4-HD and IIV3-HD were similar.ConclusionsAdding a second B strain in IIV4-HD resulted in improved immunogenicity against the added strain without compromising the immunogenicity of the other strains or the vaccine’s tolerability.Clinical trial registration: NCT03282240.     

A Phase II,randomized, immunogenicity and safety study of a quadrivalent meningococcal conjugate vaccine,MenACYW-TT,in healthy adolescents in the United States

BackgroundMenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for use in individuals ≥6 weeks of age. We evaluated the safety and immunogenicity of MenACYW-TT when compared to a licensed quadrivalent conjugate meningococcal vaccine (Menveo®; MCV4-CRM; GlaxoSmithKline, Italy), and when co-administered with tetanus, diphtheria, acellular pertussis (Tdap) and human papilloma virus (HPV4) vaccines in healthy meningococcal vaccine-naïve adolescents (10–17 years old) in the United States of America.MethodsIn this pivotal Phase II, open-label, multicenter study, 1715 participants were randomized to receive MenACYW-TT, MCV4-CRM, MenACYW-TT co-administered with Tdap and HPV4, or Tdap and HPV4 vaccines alone (NCT02199691).The primary objective was to evaluate whether antibody responses to MenACYW-TT antigens were non-inferior to antibody responses after MCV4-CRM administration. Meningococcal antibody titers were determined using human complement serum bactericidal assay (hSBA) with titers measured at baseline, and 30 days post vaccination (D30). A vaccine seroresponse was defined as baseline titers <1:8 with post-vaccination titers ≥1:8 or baseline titers ≥1:8 with a ≥4-fold increase at post-vaccination. Safety data were collected up to six months post-vaccination.ResultsNon-inferiority was demonstrated for MenACYW-TT vs MCV4-CRM (primary endpoint), and for MenACYW-TT co-administered with Tdap and HPV4 vs MenACYW-TT alone (secondary endpoint). The vaccine seroresponse rate was higher with MenACYW-TT than with MCV4-CRM, for each serogroup: A: 75.6% vs 66.4%; C: 97.2% vs 72.6%; W: 86.2% vs 66.6%; Y: 97.0% vs 80.8%. The safety profiles of MenACYW-TT, MCV4-CRM, and Tdap and HPV4 vaccines, administered with or without MenACYW-TT, were comparable. There were no vaccine-related serious adverse events.ConclusionsThe MenACYW-TT vaccine was well tolerated and generated an immune response that was non-inferior to the licensed MCV4-CRM vaccine. Immunogenicity and safety profiles were comparable when MenACYW-TT was administered with or without Tdap and HPV4 vaccines in meningococcal vaccine-naïve adolescents.     

四价流感病毒裂解疫苗安全性和免疫原性研究

目的探讨四价流感病毒裂解疫苗的安全性和免疫原性。方法使用世界卫生组织推荐的北半球疫苗株制备四价流感病毒裂解疫苗,检定合格后,用于开展全面的动物毒理试验和免疫原性研究。结果ICR小鼠毒理试验结果显示,疫苗最大耐受量MTD大于1200μg/kg;家兔免疫原性试验结果显示,血凝抑制抗体滴度大于1:40,阳转率达到100%,血清中的中和抗体能够保护鸡胚不受流感病毒感染。结论动物试验表明,该疫苗显示出良好的安全性和免疫原性。     

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects,assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN).MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination.ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups.ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.     

Quadrivalent HPV vaccine effectiveness against anogenital warts: A registry-based study of 2,2 million individuals

BackgroundIn 2009, Norway initiated routine quadrivalent HPV (qHPV) vaccination for girls at 12–13 years of age to protect against virus types causing cervical cancer, HPV16/18, and HPV6/11 which cause anogenital warts (AGW). We wanted to investigate qHPV vaccine effectiveness (VE) against AGW in females before and after first AGW episode and to assess the impact of female vaccination in males.Materials and methodsQHPV vaccination and AGW episodes were collected for the time period 2006–2016 for birth cohorts 1975–2003. Cox models were applied to age at first, as well as at second AGW episode. Finally, we estimated the impact of the female vaccination program on unvaccinated males.ResultsThe VE against the first episode of AGW was strongly dependent on vaccination age, with hazard ratios (HRs) compared to unvaccinated individuals of 0.2, 0.2, 0.3, 0.5, 1.0, 1.3, and 2.7, for age groups of ⩽13, 14–15, 16–17, 18–19, 20–24, 25–29, and 30+ years at first vaccination, respectively. Among women who had suffered a first episode of AGW, subsequent qHPV vaccination did not protect against a second episode, with HRs of 0.8, 1.0, and 1.4, for age groups of ⩽17, 18–24, and 25+ years at first vaccination. A gradually decreasing AGW risk was seen in unvaccinated male cohorts neighboring the first routinely vaccinated female 1997 cohort.ConclusionsWhen administered before 14 years of age, qHPV vaccination reduced the probability of AGW about fivefold. The effect decreased sharply with vaccination age, and was not significant among women vaccinated after age 20 years. QHPV administered after the first AGW episode did not protect against a second AGW episode. Herd effects were indicated in unvaccinated males, as we observed a gradual decrease in AGW rates from the 1993 male birth cohort and onwards.     

HPV-specific antibodies at the oral cavity up to 30 months after the start of vaccination with the quadrivalent HPV vaccine among mid-adult aged men

BackgroundHPV-16 and HPV-18 cause most oropharyngeal cancers, which are increasing in incidence among males. Although HPV vaccines are highly effective against a number of HPV-associated cancers, efficacy for oropharyngeal cancers has not yet been demonstrated. In addition, the level of antibodies required for protection against oral HPV infection is unknown.Methods150 men ages 27–45 years from Tampa, FL, USA, and Cuernavaca, Mexico, received Gardasil at Day 1, Months 2, and 6. Then, sera and oral gargles were collected one month, 12 months, and 24 months after completion of the three doses (Month 7, 18 and 30 of the study) and tested for anti-HPV-16 and HPV-18 IgG antibody levels by a L1 VLP ELISA.ResultsAll participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies and most had detectable antibodies in oral gargles at Month 7 (HPV-16: 93.2%; HPV-18: 72.1%). By months 18 and 30, oral antibodies were detectable in a lower number of participants (HPV-16, 39.8% and 29.6%; HPV-18, 10.7% and 4.6% of individuals, respectively). Overall, oral HPV-16- and 18-specific antibody levels, normalized to total IgG at months 7, 18, and 30, correlated with serum levels (HPV-16, R² = 0.93; HPV-18, R² = 0.91).ConclusionsReduced detectability of oral and serum HPV-16 and HPV-18 antibodies was observed at months 18 and 30 after initiation of the quadrivalent vaccination. However, when detectable, serum and oral HPV-16 and HPV-18 antibody levels were strongly correlated.     

A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men

BackgroundA nine-valent human papilloma virus (9vHPV) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 (as per the licensed quadrivalent HPV (qHPV) vaccine) as well as to five additional oncogenic HPV types (HPV 31/33/45/52/58). The 9vHPV vaccine has the potential to prevent 90% of cervical cancers, HPV-related anal, vaginal and vulval cancers and anogenital warts. We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 16–26-year-old men.MethodsParticipants (N = 500) were randomised to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titres (anti-HPV 6/11/16/18/31/33/45/52/58) were determined by competitive Luminex immunoassay and expressed as geometric mean titres and seroconversion rates. Vaccine safety was also assessed.ResultsThe HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine. All participants receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles.ConclusionsIn addition to immune responses to HPV 31/33/45/52/58, a three-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in men aged 16–26 years. The safety profile was also similar for the two vaccines. The results from this study support extending the efficacy findings with qHPV vaccine to 9vHPV vaccine in men aged 16–26 years.NCT02114385     

Sex difference in the immunogenicity of the quadrivalent Human Papilloma Virus vaccine: Systematic review and meta-analysis

BackgroundImmunological differences between males and females in response to viral vaccines are well known. This the first review to examine them for the Human Papilloma Virus.MethodsWe conducted a systematic review and meta-analysis of the immunogenicity of the Quadrivalent Human Papilloma Virus Vaccine qHPVV. We searched Medline, Embase, and CENTRAL for trials published until September 17, 2019. Inclusion criteria were 3-doses and reporting geometric mean titers (GMTs). We performed random-effects meta-analyses and meta-regression separated by age group and sex.ResultsOur search yielded 1809 unique studies. 334 full texts were screened and data from 18 studies were extracted. Females had higher pooled geometric mean titers than males in all age groups. Log transformed GMTs in male children (<16) years were: against HPV6: 6·62 (95% CI 6·29–6·94; I² = 86·0%), against HPV11: 7·07 (95% CI 6·90–7·23; I² = 63.1%), against HPV16: 8·53 (95% CI 8·28–8·78; I² = 73·0%), and against HPV18 7·21 (95% CI 7·08–7·34; I² = 26·4%). In females: against HPV6 7·10 (95% CI 6·79–7·41; I² = 96·6%), HPV11: 7·32 (95% CI 7·15–7·50; I² = 90·6%), HPV16: 8·71 (95% CI 8·52–8·91; I² = 90·2%), and HPV18 7·35 (95% CI 7·11–7·58; I² = 92·7%). In the meta-regression, the sexual difference was significant for HPV6 (p = 0·022) with a similar tendency for HPV11 (p = 0·066) and HPV18 (p = 0·079). Immunogenicity was significantly higher in children (<16) than in adults (p < 0·001).ConclusionFemales have higher antibody titers against HPV after receiving the qHPVV than do males. The difference is bigger in low-risk HPV strains. Adjusting the doses and schedules for each sex should be explored further.     

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in healthy subjects aged 3 to 17 years old: A phase III,open label,single-arm study

BackgroundQuadrivalent influenza vaccines are particularly valuable during seasons in which a mismatch occurs between the predicted influenza B lineage for the trivalent influenza vaccine and the circulating strain. This study evaluated the immunogenicity and safety of a quadrivalent inactivated influenza vaccine AdimFlu-S manufactured in Taiwan for the 2016–2017 influenza season in healthy children.MethodsA total of 174 healthy children aged 3 to 17 years old were separated into 3 groups (Group A: 3–8 years old, vaccine naïve; Group B: 3–8 years old, vaccine non-naïve; Group C: 9–17 years old, any vaccine status). Sera was collected pre and post vaccination for each participant. A hemagglutination inhibition (HAI) assay was utilized to calculate geometric mean titer (GMT), seroprotection rate, and seroconversion rate.ResultsAll enrolled participants completed the study. For the four vaccine strains four weeks after the last vaccination, geometric mean titer ratios (GMTRs) were between 2.9 and 20.9, seroconversion rates were between 42.9% and 90.9%, and seroprotection rates were all above 96.4%. This achieved all immunogenicity endpoints and fulfilled the criteria of the European Medical Agency’s Committee for Medicinal Products for Human Use (CHMP). No serious adverse events (AEs) were reported during the follow-up period of 6 months.ConclusionThis quadrivalent influenza vaccine is demonstrated to be well tolerated and displays robust immunogenicity for each influenza strain. This could potentially improve protection against the antigenically distinct B/Yamagata and B/Victoria lineages.     

A Phase 1, double-blind,randomized, placebo-controlled study to evaluate the safety and immunogenicity of a tetravalent live attenuated dengue vaccine in adults

BackgroundDengue fever is an important public health problem, especially in Asia and South America. A tetravalent live attenuated dengue vaccine was manufactured in India after receipt of vaccine strains from NIAID, NIH, USA.MethodsThis was a Phase 1, double-blind, randomized, placebo-controlled study performed in 60 healthy adults of 18 to 45 years. Participants were randomized 2:1 to receive a single subcutaneous injection of either a tetravalent live attenuated dengue vaccine or placebo. Safety was assessed by unsolicited adverse events (AEs) and solicited reactions through 21 days after vaccination and serious adverse events (SAEs) through the entire study period of 180 days. Dengue viremia was assessed at baseline and on day 9, 11 and 13 post-vaccination using a plaque assay. Immunogenicity was assessed using the plaque reduction neutralization test (PRNT) assay using vaccine-matched wild virus serotypes (DENV 1, DENV 2, DENV 3 and DENV 4) at baseline and on 56-, 84- and 180-days post-vaccination. PRNT assay using circulating wild type DENV 1, DENV 2, DENV 3 and DENV 4 were done on day 1 and day 85 for a subset of 31 participants.Results60 participants were randomized to receive dengue vaccine (n = 40) or placebo (n = 20). 23 participants (59 %) showed DENV vaccine viremia post- vaccination for any of the four serotypes with majority on day 9 and day 11. At baseline, all participants were naïve by dengue PRNT₅₀ for all four serotypes in both the study groups except for four in the dengue vaccine group and two in the placebo group. On day 57, the GMTs of neutralizing antibodies ranged from 66.76 (95 % CI 36.63, 121.69) to 293.84 (95 % CI 192.25, 449.11) for all four serotypes in the dengue vaccine group. On day 181 though the titers declined, they still remained much higher than the baseline. The titers in the placebo group did not change after vaccination. Seroconversion through day 85 ranged from 79.5 % for DENV 1 to 100 % for DENV2 while in the placebo group, no participant showed seroconversion through day 85. Similar trends were noted when PRNT was done using wild DENV serotypes in both vaccine and placebo groups.Among solicited reactions, injection site erythema, rash, headache, fatigue, myalgia and arthralgia were reported more frequently in the vaccine group than placebo group. All solicited reactions were of grade 1 or grade 2 severity and completely resolved. One unrelated serious adverse event was reported in the vaccine group.ConclusionA single dose of dengue vaccine was safe and well tolerated in adults. The vaccine was highly immunogenic with trivalent or tetravalent seroconversion and seropositivity in most of the participants.The study was funded by Serum Institute of India Pvt. Ltd., Pune, India. ClinicalTrials.gov: NCT04035278.     

A single dose of quadrivalent human papillomavirus (HPV) vaccine is immunogenic and reduces HPV detection rates in young women in Mongolia,six years after vaccination

BackgroundEmerging observational evidence suggests a single-dose of human papillomavirus (HPV) vaccine may be protective against vaccine-targeted HPV infection and associated cervical dysplasia. We aimed to demonstrate whether a single dose of quadrivalent HPV (4vHPV) vaccine was immunogenic and reduced HPV detection rates in young women in Mongolia. We also assessed knowledge and attitudes regarding HPV and the HPV vaccine.MethodsA retrospective paired cohort study was undertaken to evaluate the effect of a single dose of 4vHPV, given at age 11–17 years in 2012, on HPV detection rates, when compared with unvaccinated women. Real time PCR was performed on self-administered vaginal swabs for HPV detection. An immunological analysis detecting neutralising antibodies (NAb) to high-risk HPV (HRHPV) genotypes 16 and 18 was performed on sera from a subset of 58 participants. Questionnaires evaluated knowledge, attitudes and self-swab acceptability.FindingsA total of 475 women (mean age 20.4 years ± 1.6) were recruited; 118 vaccinated and 357 unvaccinated women. The prevalence of vaccine-targeted HRHPV16 and 18 was reduced by 92% (95%CI 44–99%) in the vaccinated (1·1%) compared with the unvaccinated (15.4%) group. The percentage of non-vaccine HPV genotypes was similar between vaccinated (26.5%) and unvaccinated (26.7%) groups. Approximately 90% and 58% of vaccinated women remained seropositive after six years for HRHPV16 and 18, respectively, with neutralising antibody levels 5- and 2-fold higher than unvaccinated women (p < 0.001).InterpretationOne dose of 4vHPV vaccine reduces vaccine-targeted HPV genotypes, six years following vaccination, with high levels of HR genotype seropositivity among young Mongolian women.     

Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: A partially-blind randomised placebo-controlled study

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18–25 years (N = 120) were stratified by CD4⁺ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix^®; GlaxoSmithKline Vaccines) or placebo (Al[OH]₃) at 0, 1 and 6 months (double-blind). HIV-negative women (N = 30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4⁺ T-cell responses, CD4⁺ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4⁺ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4⁺ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4⁺ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection.