Relative Vaccine Effectiveness of Cell- vs Egg-Based Quadrivalent Influenza Vaccine Against Test-Confirmed Influenza Over 3 Seasons Between 2017 and 2020 in the United States.

Background: Influenza vaccine viruses grown in eggs may acquire egg-adaptive mutations that may reduce antigenic similarity between vaccine and circulating influenza viruses and decrease vaccine effectiveness. We compared cell- and egg-based quadrivalent influenza vaccines (QIVc and QIVe, respectively) for preventing test-confirmed influenza over 3 US influenza seasons (2017-2020). Methods: Using a retrospective test-negative design, we estimated the relative vaccine effectiveness (rVE) of QIVc vs QIVe among individuals aged 4 to 64 years who had an acute respiratory or febrile illness and were tested for influenza in routine outpatient care. Exposure, outcome, and covariate data were obtained from electronic health records linked to pharmacy and medical claims. Season-specific rVE was estimated by comparing the odds of testing positive for influenza among QIVc vs QIVe recipients. Models were adjusted for age, sex, geographic region, influenza test date, and additional unbalanced covariates. A doubly robust approach was used combining inverse probability of treatment weights with multivariable regression. Results: The study included 31 824, 33 388, and 34 398 patients in the 2017-2018, 2018-2019, and 2019-2020 seasons, respectively; ∼10% received QIVc and ∼90% received QIVe. QIVc demonstrated superior effectiveness vs QIVe in prevention of test-confirmed influenza: rVEs were 14.8% (95% CI, 7.0%-22.0%) in 2017-2018, 12.5% (95% CI, 4.7%-19.6%) in 2018-2019, and 10.0% (95% CI, 2.7%-16.7%) in 2019-2020. Conclusions: This study demonstrated consistently superior effectiveness of QIVc vs QIVe in preventing test-confirmed influenza over 3 seasons characterized by different circulating viruses and degrees of egg adaptation.

Estimates of Seasonal Influenza Burden That Could Be Averted by Improved Influenza Vaccines in the Australian Population Aged Under 65 Years, 2015-2019.

BACKGROUND: The interpretation of relative vaccine effectiveness (rVE) of improved influenza vaccines is complex. Estimation of burden averted is useful to contextualise their potential impact across different seasons. For the population aged under 65 years in Australia, this study estimated the additional morbidity and mortality that could be averted using improved influenza vaccines. METHODS: We used observed, season-specific (2015-2019) influenza notification and influenza-coded hospitalisation frequencies and published modelled estimates of influenza-associated hospitalisations and deaths that occurred under the prevailing influenza vaccination coverage scenario. After back-calculating to the estimated burden in the population without vaccination, we applied published standard influenza vaccine effectiveness and coverage estimates to calculate the burden potentially averted by standard and improved influenza vaccines. A plausible range of rVE values were used, assuming 50% coverage. RESULTS: The percentage point difference in absolute vaccine effectiveness (VE) of an improved vaccine compared to a standard vaccine is directly proportional to its rVE and inversely proportional to the effectiveness of the standard vaccine. The incremental burden averted by an improved vaccine is a function of both its difference in absolute VE and the severity of the influenza season. Assuming an rVE of 15% with 50% coverage, the improved vaccine was estimated to additionally avert 1517 to 12,641 influenza notifications, 287 to 1311 influenza-coded hospitalisations and 9 to 33 modelled all-cause influenza deaths per year compared to the standard vaccine. CONCLUSIONS: Improved vaccines can have substantial clinical and population impact, particularly when the effectiveness of standard vaccines is low, and burden is high.

Early impact of the Australian national shingles vaccination program with the herpes zoster live attenuated vaccine.

Herpes zoster (shingles) is a painful condition resulting from reactivation of latent varicella zoster virus (VZV). The Australian National Shingles Vaccination Program (commenced November 2016) provides free herpes zoster vaccination for eligible adults aged 70 years, with a 5-year catch-up program (until October 2021) for adults aged 71-79 years. Patterns and impact of the program were evaluated by analysis of vaccine distribution and delivery data and specific antiviral prescription data from the Pharmaceutical Benefits Scheme. During the first 2 years, uptake of funded live attenuated shingles vaccine ZOSTAVAX® (Zoster Virus Vaccine Live; ZVL) was high across the ongoing and catch-up programs. Before program implementation (2006-2016), herpes zoster coded antiviral prescription rates increased by 2.2% per year (95% CI: 1.5, 2.9) in the 70-79 years age group. In the two years since program launch, herpes zoster antiviral prescription rates declined substantially in this age group, by an average of 13.6% per year (95% CI: 1.5, 24.2). These results indicate that the National Shingles Vaccination Program has been highly successful in vaccinating a considerable proportion of Australian adults aged 70-79 years against herpes zoster and suggest that vaccine uptake was associated with decreased incidence of herpes zoster.

Geographical clustering of anal cancer incidence in Australia.

INTRODUCTION: Homosexual men are at an increased risk of anal cancer. We aimed to establish the burden of anal squamous cell carcinoma (SCC) in those parts of Australia where homosexual men are most likely to live. METHODS: Data on the proportion of homosexual male residents were obtained from published estimates. Men were categorised into three postcode groups by prevalence of men reporting homosexual identity. Male population data in age groups were extracted for each postcode group and analyses of cancer incidence were performed by postcode group. The analyses were restricted to 2000-2005. RESULTS: Eight postcodes had populations where more than 10% of males reported homosexual identity (high prevalence) and 4-10% of men reported homosexual activity in a further 19 postcodes (medium prevalence). From 2000 to 2005, the average annual age-standardised incidence rates of anal SCC in males was 7.61 per 100000 (95% confidence interval (CI): 4.68-10.55) and 2.21 per 100000 (95% CI: 1.05-3.37) in high and medium prevalence postcodes, respectively. The corresponding incidence rate ratios compared with low prevalence postcodes (less than 4% of males reported homosexual identity) were 9.6 (95% CI: 6.6-14.1) for the high prevalence and 2.4 (95% CI: 1.4-4.1) for the medium prevalence postcodes. CONCLUSION: A substantial concentration of the burden of anal cancer occurred among areas where large proportions of homosexual men reside. These results should guide the prioritisation of health service investment in anal cancer treatment and prevention to appropriate geographical areas.

Trends in anal cancer in Australia, 1982-2005.

BACKGROUND: Most anal squamous cell carcinomas (SCCs) are caused by high risk types of human papillomavirus (HPV) and are potentially preventable by HPV vaccination. In order to understand the burden of potentially preventable anal cancer in Australia, we examine the incidence and survival from invasive anal SCC 1982-2005. METHODS: We reviewed data on invasive anal cancer cases notified to the National Cancer Statistics Clearing House. Age specific incidence rates of SCC were calculated by year of cancer diagnosis and by birth cohort, and rates of anal adenocarcinoma were included for comparison. Incidence rates were age standardised to the Australian 2001 standard population. Trends in relative survival of SCC were examined. RESULTS: During the study period, a total of 4615 invasive anal cancer cases were diagnosed and most (69.7%) were SCC. Annual incidence of SCC increased almost 50%, from 0.65 to 1.00/100,000. Incidence increased at all ages. The annual rate of increase was almost two-folder higher in men (3.42%, 95% CI 2.49-4.35) than in women (1.88%, 95% CI 1.18-2.58). Five-year relative survival increased by nearly 10% from 58.9% to 68.3% over the last 20 years. Younger patients and women had better survival. For anal adenocarcinoma, increases of borderline significance were seen in men and women. CONCLUSION: There is an increasing burden of anal SCC in Australia. The group with the highest incidence - homosexual men - are not likely to be protected under the current vaccination policy.

Cancers attributable to human papillomavirus infection.

Although the human papillomavirus (HPV) vaccine was introduced primarily as a cervical cancer prevention vaccine, HPV has a causal role in several types of cancer. This article reviews the epidemiological evidence for the role of HPV in human cancer, and describes Australian trends in these cancers. HPV is a necessary cause of cervical cancer. The currently vaccine-preventable subtypes of HPV 16 and 18 are responsible for ~70% of cervical cancer. The introduction of an organised Pap smear program in Australia led to a steep decline in incidence over the past decades. HPV can be detected in ~40% and 70% of vulval and vaginal cancers respectively. Rates of these cancers have been stable over the past 20 years. The prevalence of HPV in penile cancer is ~50% and incidence has not recently changed. For anal cancer, ~85% of cases are HPV positive, and incidence has increased significantly in both men and women over the past 20 years. In the oral cavity, ~35% of oropharyngeal cancers and ~25% of other oral cavity cancers are HPV positive. The incidence of HPV-related oral cavity and oropharyngeal cancers is increasing, whereas incidence at HPV-unrelated sites is decreasing. Overall, 1154 HPV-related cancer cases were potentially preventable by vaccination. If HPV-related cancers at non-cervical sites are prevented by vaccination, then a similar number of cancer cases will be prevented as in the cervix. However, almost one-quarter of the potentially preventable cancer cases are in men, who are not included in the current national immunisation program.

Genital warts incidence and healthcare resource utilisation in Australia.

OBJECTIVES: To estimate for the first time the incidence and healthcare resource utilisation associated with genital warts (GW) in Australia prior to the human papillomavirus vaccination programme. METHOD: The authors analysed data from the nationally representative Bettering the Evaluation of Care and Health general practice cross-sectional programme and from the National Hospital Morbidity Database to estimate age-related incidence and community (non-hospital) and hospital-related costs (in 2009 Australian dollars) associated with medical treatment of GW. RESULTS: The authors estimated an annual incidence of 2.19 cases of GW per 1000 Australians (95% CI 1.88 to 2.49), with peak incidence in women aged 20-24 years at 8.61 cases per 1000 and in men aged 25-29 years at 7.40 cases per 1000. The estimated number of consultations per GW case was 2.9 (95% CI 2.5 to 3.3) for women and 2.8 (95% CI 2.3 to 3.2) for men. Ablative treatments in general practice were more common in men (60% of consultations) than in women (37% of consultations). In contrast, more women (16% vs 8%) were referred to specialists, and 75% of ablative procedures requiring hospitalisation were performed in women. The annual cost of management of GW is over A$14 million, with an estimated cost per treated case of A$251 for men and A$386 for women. CONCLUSIONS: GW impose a large health and cost burden on Australians. The national immunisation programme with the quadrivalent human papillomavirus vaccine has the potential to greatly reduce this burden, and future research measuring its impact is keenly anticipated.

Patterns of treatment of external genital warts in Australian sexual health clinics.

BACKGROUND: External genital warts are a common sexually transmitted viral disease. We describe the patterns of treatment for initial presentations of external genital warts (EGWs) in Australian sexual health centers. METHODS: This was a retrospective audit of 489 case notes from consecutive individuals who presented with a new diagnosis of EGWs to 1 of 5 major sexual health clinics in Australia. Eligibility criteria were consecutive patients aged 18 to 45 years inclusively, presenting with first ever episode of EGWs from January 1, 2004. Exclusion criteria were patients who were immunocompromised, including HIV infection, or enrollment in a treatment study for EGWs. RESULTS: The median age at presentation of women was 23.2 years and of men 26.8 years. One quarter (n = 127) of patients had another sexually transmitted infection diagnosed at presentation. Nearly half of the patients (n = 224) presented only once for treatment. Most often, patients were treated with a monotherapy (n = 382/489; 78%), usually cryotherapy (257; 53%). Staff applied treatment in 361 (74%) cases. There was wide variation across sites, possibly reflecting local policies and budgets. We found no difference in wart resolution (n = 292; 60%) by initial treatment chosen. CONCLUSIONS: The diagnosis and treatment of genital warts constitute a sizable proportion of clinical visits to the audited sexual health services and require a large input of staff time to manage, including the application of topical treatments. Our results help complete the picture of the burden of EGWs on Australian sexual health centers before the introduction of the HPV vaccine.

Herpes zoster burden of illness and health care resource utilisation in the Australian population aged 50 years and older.

Incidence of zoster and post-herpetic neuralgia (PHN) and associated health care resource utilisation were investigated in the Australian population aged > or =50 years, using general practice data from 2000 to 2006, and pharmaceutical prescribing, hospital morbidity and emergency department data from 1998 to 2005. Zoster and PHN incidence rates were estimated as approximately 10/1000 and 1.45/1000 persons, respectively, with antivirals prescribed for 73.5% of zoster cases. Estimated hospitalisation and emergency department visit rates were 0.67/1000 and 0.38/1000 persons, respectively. Management of zoster (including PHN) involved approximately 2.4 general practitioner consultations. Total costs to the health care system were estimated as approximately 32.8 million per year. The substantial burden of zoster and PHN highlights the potential benefit of zoster vaccination.

Late onset antibody-mediated rejection and endothelial localization of vascular endothelial growth factor are associated with development of cardiac allograft vasculopathy.

BACKGROUND: Improvements in cardiac transplant practice and immunosuppressive treatment have done much to curb the incidence of acute cellular rejection (ACR); however, antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) remain prevalent. Recent studies have shown that allograft rejection is governed by both allogeneic and nonallogeneic factors such as inflammation. Initial studies have suggested that vascular endothelial growth factor (VEGF), a leukocyte mitogen produced by activated endothelial cells and leukocytes, may play a specific role in not only leukocyte trafficking, but also in the augmentation of ACR and development of CAV. METHODS: We investigated the localization of VEGF protein using immunohistochemistry in a cohort of 76 heart transplant patients during periods of ACR and AMR and assessed the development of CAV. RESULTS: We showed a significant correlation between lymphocytic localization of VEGF protein and severe ACR (P<0.001). Antibody-mediated rejection positive biopsies taken at 12 months posttransplantation showed significantly greater endothelial localization of VEGF than time-matched AMR negative biopsies (P=0.006). Diffuse endothelial expression of VEGF was also associated with a 2.5-fold increase in the risk of developing CAV (P=0.001). CONCLUSIONS: These results show that localization of VEGF protein to the vascular endothelium during AMR is significantly increased in patients who develop CAV. This study also highlights the potential pathogenic role of the endothelial cell in late onset AMR and the development of CAV.

Increased vascular endothelial growth factor mRNA in endomyocardial biopsies from allografts demonstrating severe acute rejection: a longitudinal study.

Investigation into the contribution of the immune system and inflammatory cascade to acute rejection (AR) and cardiac allograft vasculopathy (CAV) has implicated vascular endothelial growth factor (VEGF). The endomyocardial biopsy (EB) has proved invaluable in the diagnosis of AR, and in providing information concerning the biological processes occurring following transplantation. The association between VEGF and AR and the development of CAV was examined in endomyocardial biopsies (EBs) from a cohort of 76 heart transplant recipients. VEGF mRNA levels were quantified through real time RT-PCR in 712 EBs, obtained at routine intervals during post-operative monitoring. VEGF and leukocyte and endothelial markers were assessed in a subset of biopsies through immunohistochemistry. The results of generalised linear modelling, adjusting for covariates, revealed VEGF mRNA expression was 19% greater during severe AR as compared to no rejection (p=0.007). Immunohistochemical results supported these findings. Mean VEGF mRNA levels were not significant predictors for the development of CAV (p=0.554). However the risk of cardiac related death increased 9-fold for a 1 unit increase in mean VEGF expression (p=0.006). Similarly, a single unit increase in mean AR severity equated to a 10-fold increase in the risk of cardiac related death (p<0.005). Our data suggest that increased VEGF expression is strongly associated with severe AR and cardiac related death.

Beyond operational tolerance: effect of ischemic injury on development of chronic damage in renal grafts.

BACKGROUND: The induction of operational tolerance is the holy grail of clinical transplantation. However, in animal models with operational tolerance, long- term grafts still develop chronic damage. The elucidation of the impact of allogenic versus nonallogeneic factors in such a model is important. This study examined the effect of a clinically relevant combination of warm ischemia and cold preservation in the absence of allogeneic response (isografts) and in the context of operational tolerance. METHODS: Dark Agouti (DA) rat kidneys were transplanted into DA recipients (isografts) or Albino Surgery recipients (allografts) tolerized by two transfusions of DA blood, under cover of cyclosporin A. Grafts were subjected to minimal cold preservation or to 30 mins warm ischemia followed by 24 hrs cold preservation. RESULTS: After an initial peak of renal dysfunction, serum creatinine concentration returned to normal in isografts and nonischemic allografts, but remained significantly elevated in ischemic allografts (P<0.0002) throughout 6 months follow-up. Both allograft groups developed proteinuria. At 6 months, ischemic isografts and nonischemic allografts demonstrated very mild tubular atrophy and interstitial fibrosis. Tubulointerstitial injury was significantly more severe in ischemic allografts (P<0.01 vs. nonischemic allografts) and was associated with increased infiltrating monocyte/macrophages and NK cells (P<0.05). Moderate glomerulosclerosis was a feature of both allograft groups (P<0.05). CONCLUSIONS: The modified allogeneic response in operationally tolerant recipients acts in synergy with ischemia/reperfusion injury in the development of chronic damage. Strategies to limit or modify the initial ischemia/reperfusion injury may ameliorate chronic tubulointerstitial damage. Progressive glomerular damage and proteinuria in allografts may require other pharmacological intervention.