Testing fractional doses of COVID-19 vaccines.

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that, even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggests strong interest in these approaches.

Frequency and Cost of Vaccinations Administered Outside Minimum and Maximum Recommended Ages-2014 Data From 6 Sentinel Sites of Immunization Information Systems.

OBJECTIVE: To quantify vaccinations administered outside minimum and maximum recommended ages and to determine attendant costs of revaccination by analyzing immunization information system (IIS) records. STUDY DESIGN: We analyzed deidentified records of doses administered during 2014 to persons aged <18 years within 6 IIS sentinel sites (10% of the US population). We quantified doses administered outside of recommended ages according to the Advisory Committee on Immunization Practices childhood immunization schedule and prescribing information in package inserts, and calculated revaccination costs. To minimize misreporting bias, we analyzed publicly funded doses for which reported lot numbers and vaccine types were consistent. RESULTS: Among 3 394 047 doses with maximum age recommendations, 9755 (0.3%) were given after the maximum age. One type of maximum age violation required revaccination: 1344 (0.7%) of 194 934 doses of the 0.25-mL prefilled syringe formulation of quadrivalent inactivated influenza vaccine (Fluzone Quadrivalent, Sanofi Pasteur, Swiftwater, PA) were administered at age ≥36 months (revaccination cost, $111 964). We identified a total of 7 529 165 childhood, adolescent, and lifespan doses with minimum age recommendations, 9542 of which (0.1%) were administered before the minimum age. The most common among these violations were quadrivalent injectable influenza vaccines (3835, or 0.7% of 526 110 doses administered before age 36 months) and Kinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium; DTaP-IPV) (2509, or 1.2% of 208 218 doses administered before age 48 months). The cost of revaccination for minimum age violations (where recommended) was $179 179. CONCLUSION: Administration of vaccines outside recommended minimum and maximum ages is rare, reflecting a general adherence to recommendations. Error rates were higher for several vaccines, some requiring revaccination. Vaccine schedule complexity and confusion among similar products might contribute to errors. Minimization of errors reduces wastage, excess cost, and inconvenience for parents and patients.

Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization.

A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities.

Determining the Optimal Vaccination Schedule for Herpes Zoster: a Cost-Effectiveness Analysis.

BACKGROUND: The Advisory Committee on Immunization Practices recommends a single dose of herpes zoster (HZ) vaccine in persons aged 60 years or older, but the efficacy decreases to zero after approximately 10 years. A booster dose administered after 10 years might extend protection, but the cost-effectiveness of a booster strategy has not been examined. OBJECTIVE: We aimed to determine the optimal schedule for HZ vaccine DESIGN: We built a Markov model to follow patients over their lifetime. From the societal perspective, we compared costs and quality-adjusted life years (QALYs) saved of 11 strategies to start and repeat HZ vaccine at different ages. SUBJECTS: Adults aged 60 years. INTERVENTION: HZ vaccine. MAIN MEASURES: Costs, quality-adjusted life years (QALYs), and incremental costs per QALY saved. KEY RESULTS: At a $100,000/QALY threshold, "vaccination at 70 plus one booster" was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of $36,648/QALY. "Vaccination at 60 plus two boosters" was more effective, but had an ICER of $153,734/QALY. In deterministic sensitivity analysis, "vaccination at 60 plus two boosters" cost < $100,000/QALY if compliance rate was > 67 % or vaccine cost was < $156 per dose. In probabilistic sensitivity analysis, "vaccination at 70 plus one booster" was preferred at a willingness-to-pay of up to $135,000/QALY. CONCLUSIONS: Under current assumptions, initiating HZ vaccine at age 70 years with one booster dose 10 years later appears optimal. Future data regarding compliance with or efficacy of a booster could affect these conclusions.

Cutaneous varicella zoster virus infection following zoster vaccination: report of post-vaccination herpes zoster skin infection and literature review of zoster vaccination efficacy and guidelines.

BackgroundHerpes zoster vaccine is currently recommended in the United States for immune competent individuals ≥60 years. The efficacy of the herpes zoster vaccine decreases with age and with time following vaccination.PurposeAn elderly man with herpes zoster following vaccination is described. The guidelines for vaccination and issues regarding re-vaccination are reviewed. METHODS: PubMed was used to search the following terms: efficacy, elderly, herpes zoster, herpes zoster incidence, herpes zoster recurrence, and vaccination. The papers and relevant citations were reviewed. The clinical features of a patient with post-vaccination herpes zoster skin infection are presented; in addition, vaccine efficacy and guidelines are reviewed.ResultsA 91-year-old man, vaccinated for herpes zoster 10 years earlier, presented with crusted erosions on his face corresponding to the area innervated by the ophthalmic division of the left trigeminal nerve. Evaluation using polymerase chain reaction confirmed the diagnosis of herpes zoster.ConclusionsHerpes zoster vaccine decreases in efficacy with both age and number of years following vaccination. Therefore, booster shots or revaccination in the older population may be of benefit.

Economic evaluation of second measles containing vaccine (MCV) dose: a systematic review of available evidence.

INTRODUCTION: The global measles incidence has decreased from 145 to 49 cases per 1 million population from 2000 to 2018, but evaluating the economic benefits of a second measles-containing vaccine (MCV2) is crucial. This study reviewed the evidence and quality of economic evaluation studies to guide MCV2 introduction. METHODS: The systematic review of model-based economic evaluation studies was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search yielded 2231 articles, with 876 duplicates removed and 1355 articles screened, with nine studies included for final analysis. RESULTS: Six studies reported a positive benefit-cost ratio with one resulting in net savings of $11.6 billion, and two studies estimated a 2-dose MMR vaccination program would save $119.24 to prevent one measles case, and a second dose could prevent 9,200 cases at 18 months, saving $548.19 per case. The most sensitive variables were the discount rate and vaccination administration cost. CONCLUSIONS: Two MCV doses or a second opportunity with an additional dose of MCV were highly cost-beneficial and resulted in substantial cost savings compared to a single routine vaccine. But further research using high-quality model-based health economic evaluation studies of MCV2 should be made available to decision-makers. PROSPERO REGISTRATION: CRD42020200669.

[Epidemiological and economic impact of tetanus vaccination in Colombian adults]. / Impacto epidemiológico y económico de la vacunación contra el tétanos en adultos de Colombia.

OBJECTIVE: Assess the potential epidemiological and economic impact of vaccinating the over-15 Colombian population against tetanus with a booster dose every 10 years. METHODS: A cost-effectiveness analysis of tetanus vaccination with a booster dose every 10 years was conducted in Colombia and compared with the current strategy (2, 4, 6, 18, and 60 months). Estimates of the burden of disease were based on three official data sources. A Markov model from the perspective of the third party payer was developed. The time horizon was the lifetime of a person. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In Colombia, 30 to 48 cases of tetanus resulting in 9.6 to 10.1 deaths are reported each year. Although booster vaccination for the entire population was cost-effective (the cost per disability-adjusted life year [DALY] avoided was US$ 11,314 in the entire population), gender-based differentiation of the results showed that it would not be cost-effective in women (cost per DALY avoided was US$ 4,903 in men and US$ 22,332 in women). CONCLUSIONS: This is the first study that evaluates the cost-effectiveness of a tetanus vaccine booster dose every 10 years in a developing country. Use of this measure would be cost-effective in Colombia, especially for men. As a result of the gender-based differences in the results, any decision about its use in women of childbearing age should take current vaccination into account.

[Indirect, population effect of mass pneumococcal vaccinations (PCV7) on all-cause pneumonia incidence in Kielce, Poland]. / Posredni, populacyjny wplyw powszechnych szczepien skoniugowana szczepionka pneumokokowa (PCV7) na czestosc zachorowan na zapalenie pluc w Kielcach.

In these article they made analysis of indirect, population effects of mass, free of charge, pneumococcal vaccinations (PCV7) on all-cause pneumonia incidence in Kielce, Poland. The strongest and significant fall (p=0.00079) in all-cause pneumonia incidence in the analyzed period 2005-2009 compared with remaining groups were observed in the group of children under 2 of years of life. He amounted to the 74% (around 25/1000 in 2005; 6/1000 in 2009). In the entire ancient group 0-29, embracing children under 2 yrs of life the fall of pneumonia incidence rate amounted to the 48% (from 2.8/1000 in 2005; 1.5/1000 in 2009). In the age 65+ group the fall in the incidence amounted to the 45% (19/1000 in 2005; <11/1000 in 2009 r.). At the moment they didn't observe, of such a fall in age groups 30-49 yrs and 50-64 yrs. Presented results are pointing population effectiveness of applied in Kielce mass vaccination in a 2+1 scheme. Analyzing only pneumonia requiring the hospitalization they tried at work to estimate, in the definitely simplified way, financial effects of mass pneumococcal vaccination in Kielce. Analysis showed at children up to 2 yrs frugalities of the row of the 174,420 zloty annually. In the group above 1 year of life analogous analysis showed frugalities of row 789,480 zloty. Results presented by us should, in our opinion, to induce decision-makers for free of charge mass pneumococcal vaccinations to entire Poland.

The distribution over time of costs and social net benefits for pertussis immunization programs.

The cost of a six-dose pertussis immunization programs for children and adolescents is investigated in relation to estimators of the price of acellular vaccine, the value of a child's life, levels of vaccination rate and discount rates. We compare the cost of the program maintained over time at 90% with three alternative strategies, each involving a decrease in vaccination coverage. Data from England and Wales, 1966-2005, is used to formalize a delay in occurrence of pertussis cases as a result of a fall in coverage. We first apply the criterion of minimization of the total social cost of pertussis to identify the best cost saving immunization strategy. The results are also discussed in form of the discounted present value of the total social net benefits. We find that the discounted present value of the total social net benefit is maximized when a stable vaccination program at 90% is compared to a gradual decrease in vaccination coverage leading to the lowest vaccination rate. The benefits to society of providing sustained immunization strategy, vaccinating the highest proportion of children and adolescents, are systematically proved on the basis of the second optimisation criterion, independently of the level of estimators applied during economic evaluation for the cost variables.

The burden of pertussis in older adults: what is the role of vaccination? A systematic literature review.

INTRODUCTION: Pertussis (whooping cough) is a vaccine-preventable disease; however, neither natural- nor vaccine-induced protection is life-long. Although generally not severe in adults, pertussis can be associated with complications in patients with chronic conditions such as asthma or chronic obstructive pulmonary disease, and can be readily transmitted to more vulnerable populations, including neonates before they complete their primary vaccination. Furthermore, as the global population ages, the health and economic burden of the disease is expected to rise. Areas covered: A systematic literature review was conducted to ascertain the current epidemiological and financial burden of pertussis in older adults and to discuss the potential value of a booster vaccination in this population. Expert commentary: Our review indicates a considerable underestimation of the pertussis burden amongst older adults. Seroprevalence studies consistently demonstrate that the reported incidence may be much lower than the actual incidence. Tetanus toxoid-reduced diphtheria toxoid and acellular pertussis vaccines are immunogenic in older adults, induce high booster responses and are well-tolerated. There is therefore a good rationale for the advocacy of booster pertussis vaccination throughout life to prevent pertussis infection and its transmission, especially in adults aged ≥50 years.

Early use of the HPV 2-dose vaccination schedule: Leveraging evidence to support policy for accelerated impact.

Although human papillomavirus (HPV) vaccines were initially licensed based on efficacy after three-dose regimens in women aged 15-26 years, it was recognized early in clinical development that comparable immunogenicity could be obtained after just two doses when administered to younger girls. In both Canada and Mexico, public health authorities made the decision to administer two doses 6 months apart with a planned additional dose at 60 months, while simultaneously doing further study to determine if the third dose would confer meaningful additional benefit. This delayed third dose approach permitted a more cost-effective program with opportunities for improved compliance while minimizing injections and leaving open the opportunity to provide a full three-dose vaccination series. It required close cooperation across many governmental and civil society leadership bodies and real-time access to emerging data on HPV vaccine effectiveness. Although still limited, there is increasing evidence that even one-dose vaccination is sufficient to provide prolonged protection against HPV infection and associated diseases. Ongoing clinical trials and ecological studies are expected to consolidate existing data regarding one dose schedule use. However, to accelerate the preventive effect of HPV vaccination some jurisdictions, in particular those with limited resources may already consider the initiation of a one dose vaccination with the possibility of giving the second dose later in life if judged necessary. Such an approach would facilitate vaccination implementation and might permit larger catch-up vaccination programs in older girls (or as appropriate, girls and boys), thereby accelerating the impact on cervical cancer and other HPV-associated diseases.

A cost-effectiveness analysis of revaccination and catch-up strategies with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in older adults in Japan.

OBJECTIVE: In Japan, the National Immunization Program (NIP) includes PPV23 as the primary vaccination for adults and catch-up cohorts. The Japanese Association for Infectious Diseases recommends revaccination for older adults who received primary vaccination ≥5 years earlier. The cost-effectiveness of adding revaccination and/or continuing catch-up vaccination in the NIP was evaluated from the public payer perspective in Japan. METHODS: The Markov model included five health states: no pneumococcal disease, invasive pneumococcal diseases (IPD), non-bacteremic pneumococcal pneumonia (NBPP), post-meningitis sequelae, and death. Cohorts of adults aged 65-95 were followed until age 100 or death: 2014 cohort (aged 65-95, vaccinated: 2014); 2019 cohort (aged 65: 2019); and 2019 catch-up cohort (aged 70-100: 2019, unvaccinated: 2014). Strategies included: (1) vaccinate 2014 and 2019 cohorts; (2) vaccinate 2014 and 2019 cohorts and revaccinate both; (3) strategy 1 and vaccinate 2019 catch-up cohort; (4) strategy 2 and vaccinate 2019 catch-up cohort; and (5) strategy 4 and revaccinate 2019 catch-up cohort. Parameters were retrieved from global and Japanese sources, costs and QALYs discounted at 2%, and incremental cost-effectiveness ratios (ICERs) estimated. RESULTS: Strategy 1 had the highest number of IPD and NBPP cases, and strategy 5 the lowest. Strategies 3-5 dominated strategy 1 and strategy 2 was cost-effective compared to strategy 1 (ICER: ¥1,622,153 per QALY gained). At a willingness-to-pay threshold of ¥5 million per QALY gained, strategy 2 was cost-effective and strategies 3-5 were cost-saving compared to strategy 1. CONCLUSIONS: Strategies including revaccination, catch-up, or both were cost-effective or cost-saving in comparison to no revaccination and no catch-up. Results can inform future vaccine policies and programs in Japan.

Combined effect of PCV10 and meningococcal C conjugate vaccination on meningitis mortality among children under five years of age in Brazil.

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in the Brazilian National Immunization Program in March 2010, scheduled at 2, 4, and 6 months, with a booster at 12-15 months of age. The meningococcal C conjugate vaccine (MCC) was introduced in November 2010, scheduled at 3 and 5 months, with a booster dose at 12-15 months of age and no catch-up for older age groups. In this interrupted time-series analysis study, we used Brazilian mortality data from 2005 to 2015 for children under five years of age (excluding data from the state of Bahia) to assess the combined impact of these vaccines on the overall burden of meningitis mortality among children aged 0-23 months and 2-4 years, as defined using meningitis and meningococcemia specific International Classification of Diseases - tenth revision codes. Secular trends and seasonality were taken into account. We found significant reductions for both age groups relative to those observed for the comparison group of diseases, with immediate effects after the transition period (2010-2011) of 29.2% and 27.5% for children aged 0-23 months and 2-4 years, respectively. These immediate effects were sustained throughout the post-vaccination period (2012-2015). In total, 337 deaths were averted by the combined effect of both vaccines, 238 (95%CI 169-319) for children aged 0-23 months and 99 (95%CI 56-144) for those aged 2-4 years. These results add strong evidence in support of investments in these vaccines by low and middle-income countries.

Cost effectiveness of a targeted age-based West Nile virus vaccination program.

BACKGROUND: West Nile virus (WNV) is the leading cause of domestically-acquired arboviral disease in the United States. Several WNV vaccines are in various stages of development. We estimate the cost-effectiveness of WNV vaccination programs targeting groups at increased risk for severe WNV disease. METHODS: We used a mathematical model to estimate costs and health outcomes of vaccination with WNV vaccine compared to no vaccination among seven cohorts, spaced at 10year intervals from ages 10 to 70years, each followed until 90-years-old. U.S. surveillance data were used to estimate WNV neuroinvasive disease incidence. Data for WNV seroprevalence, acute and long-term care costs of WNV disease patients, quality-adjusted life-years (QALYs), and vaccine characteristics were obtained from published reports. We assumed vaccine efficacy to either last lifelong or for 10years with booster doses given every 10years. RESULTS: There was a statistically significant difference in cost-effectiveness ratios across cohorts in both models and all outcomes assessed (Kruskal-Wallis test p<0.0001). The 60-year-cohort had a mean cost per neuroinvasive disease case prevented of $664,000 and disability averted of $1,421,000 in lifelong model and $882,000 and $1,887,000, respectively in 10-year immunity model; these costs were statistically significantly lower than costs for other cohorts (p<0.0001). Vaccinating 70-year-olds had the lowest cost per death averted in both models at around $4.7 million (95%CI $2-$8 million). Cost per disease case averted was lowest among 40- and 50-year-old cohorts and cost per QALY saved lowest among 60-year cohorts in lifelong immunity model. The models were most sensitive to disease incidence, vaccine cost, and proportion of persons developing disease among infected. CONCLUSIONS: Age-based WNV vaccination program targeting those at higher risk for severe disease is more cost-effective than universal vaccination. Annual variation in WNV disease incidence, QALY weights, and vaccine costs impact the cost effectiveness ratios.

Serological testing--an alternative to boosters?

The issue of the duration of immunity, particularly for the modified live viral components of veterinary vaccines, has been a significant part of the recent vaccination debate. One manufacturer has increased the recommended booster interval for these components to 3 years give name and another now states 'up to 4 years' immunity. There remain many unanswered questions regarding this duration of immunity (DOI). Studies suitable for data sheet claims are time consuming and costly and can only be performed in laboratory dogs under tightly controlled conditions. Evidence from rabies serology testing in the UK shows that the response of individual animals to routine vaccination is highly variable. Much of the published field evidence on the persistence of antibody titres originates from North America, where vaccination strategies and reservoir species differ from Europe. Quantifying the effect of exposure to field virus on the maintenance of immunity in these studies is impossible, and little is known of the circulation of virus in unvaccinated dogs and wild mammals throughout Europe. If owners or vets are concerned about revaccination one option is to assess the need for each booster by performing a blood test. There is some published evidence of the relationship between antibody titres and protective immunity, and tests are available to measure responses to individual viral components of the routine canine and feline vaccines. It must be remembered that most commercial tests to assess immunity only measure antibodies, which are only one aspect of the immune response to vaccination. It is therefore possible that animals without or with low antibody titres are in fact protected. Serological tests are an option if owners are unwilling to have their animal boostered without evidence that it is needed. However, the cost of these tests is likely to exceed that of booster vaccination for the foreseeable future.