Vaccine Efficacy Estimates Research Articles

Would vaccination against nicotine be a cost‐effective way to prevent smoking uptake in adolescents?

We used epidemiological modelling to assess whether nicotine vaccines would be a cost-effective way of preventing smoking uptake in adolescents. We built an epidemiological model using Australian data on age-specific smoking prevalence; smoking cessation and relapse rates; life-time sex-specific disability-adjusted life years lived for cohorts of 100,000 smokers and non-smokers; government data on the costs of delivering a vaccination programme by general practitioners; and a range of plausible and optimistic estimates of vaccine cost, efficacy and immune response rates based on clinical trial results. We first estimated the smoking uptake rates for Australians aged 12-19 years. We then used these estimates to predict the expected smoking prevalence in a birth cohort aged 12 in 2003 by age 20 under (i) current policy and (ii) different vaccination scenarios that varied in cost, initial vaccination uptake, yearly re-vaccination rates, efficacy and a favourable vaccine immune response rate. Under the most optimistic assumptions, the cost to avert a smoker at age 20 was $44,431 [95% confidence interval (CI) $40,023-49,250]. This increased to $296,019 (95% CI $252,307-$355,930) under more plausible scenarios. The vaccine programme was not cost-effective under any scenario. A preventive nicotine vaccination programme is unlikely to be cost-effective. The total cost of a universal vaccination programme would be high and its impact on population smoking prevalence negligible. For these reasons, such a programme is unlikely to be publicly funded in Australia or any other developed country.

Clinical study of transcutaneous vaccination using a hydrogel patch for tetanus and diphtheria

Transcutaneous immunization (TCI) is a non-invasive and easy-to-use vaccination method. We demonstrated the efficacy and safety of a transcutaneous vaccine formulation using a hydrogel patch in animal experiments. In the present study, we performed a clinical study to apply our TCI formulation for vaccination against tetanus and diphtheria in human. The TCI device was a hydrogel patch (antigen-free) applied to the left brachial medial skin of 22 healthy volunteers for 48 h. Next, the hydrogel patch, containing 2mg tetanus toxoid (TT) and 2mg diphtheria toxoid (DT) as the TCI formulation, was applied to 27 healthy volunteers for 24h and some volunteers were vaccinated again by TCI formulation. For safety assessment, the patch application site was observed to assess local adverse events, and systemic adverse events were determined by a blood test. The antigen-free hydrogel patch and TCI formulation containing TT and DT did not induce local or systemic severe adverse events. For vaccine efficacy estimation, toxoid-specific serum antibody titers were determined by ELISA and the toxin-neutralizing activity of the induced antibody was evaluated in a passive-challenge experiment. The anti-TT IgG titer and the anti-DT IgG titer increased, and a significant effect was detected by paired t-test. The antibody titers were maintained at higher level than that before vaccination for at least 1 year. Moreover, toxoid-specific antibodies were produced by the second vaccination in some subjects. Antibodies induced by application of the TCI formulation neutralized the toxin and prevented toxic death in mice. In addition, changes in the skin condition due to application of the TCI formulation were observed under in vivo confocal Raman spectroscopy. The amount of water and patch components in the stratum corneum increased after application of the TCI formulation, suggesting that the change in the skin condition was related to antigen penetration. These data indicate that this easy-to-use TCI system induces an immune response without severe adverse reactions in humans. This easy-to-use and safe TCI formulation enables mass treatment in an outbreak setting and increased vaccination rates in developing countries, and will greatly contribute to worldwide countermeasures against infectious diseases.

Causal Inference for Vaccine Effects on Infectiousness

If a vaccine does not protect individuals completely against infection, it could still reduce infectiousness of infected vaccinated individuals to others. Typically, vaccine efficacy for infectiousness is estimated based on contrasts between the transmission risk to susceptible individuals from infected vaccinated individuals compared with that from infected unvaccinated individuals. Such estimates are problematic, however, because they are subject to selection bias and do not have a causal interpretation. Here, we develop causal estimands for vaccine efficacy for infectiousness for four different scenarios of populations of transmission units of size two. These causal estimands incorporate both principal stratification, based on the joint potential infection outcomes under vaccine and control, and interference between individuals within transmission units. In the most general scenario, both individuals can be exposed to infection outside the transmission unit and both can be assigned either vaccine or control. The three other scenarios are special cases of the general scenario where only one individual is exposed outside the transmission unit or can be assigned vaccine. The causal estimands for vaccine efficacy for infectiousness are well defined only within certain principal strata and, in general, are identifiable only with strong unverifiable assumptions. Nonetheless, the observed data do provide some information, and we derive large sample bounds on the causal vaccine efficacy for infectiousness estimands. An example of the type of data observed in a study to estimate vaccine efficacy for infectiousness is analyzed in the causal inference framework we developed.

Real-time Investigation of Measles Epidemics with Estimate of Vaccine Efficacy

As part of measles elimination effort, evaluation of the vaccination program and real-time assessment of the epidemic dynamics constitute two important tasks to improve and strengthen the control. The present study aimed to develop an epidemiological modeling method which can be applied to estimating the vaccine efficacy at an individual level while conducting the timely investigation of the epidemic. The multivariate renewal process model was employed to describe the temporal evolution of infection by vaccination history, jointly estimating the time-dependent reproduction number and the vaccine efficacy. Analyzing the enhanced surveillance data of measles in Aichi prefecture, Japan from 2007-08, the vaccine efficacy was estimated at 96.7% (95% confidence interval: 95.8, 97.4). Using an age structured model, the vaccine efficacy among those aged from 5-19 years was shown to be smaller than that among those from 0-4 years. The age-dependent vaccine efficacy estimate informs the age-groups to be targeted for revaccination. Because the estimation method can rest on readily available epidemiological data, the proposed model has a potential to be integrated with routine surveillance.

Health and economic impact of PHiD-CV in Canada and the UK: a Markov modelling exercise

Objective:The spectrum of diseases caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) represents a large burden on healthcare systems around the world. Meningitis, bacteraemia, community-acquired pneumonia (CAP), and acute otitis media (AOM) are vaccine-preventable infectious diseases that can have severe consequences. The health economic model presented here is intended to estimate the clinical and economic impact of vaccinating birth cohorts in Canada and the UK with the 10-valent, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared with the newly licensed 13-valent pneumococcal conjugate vaccine (PCV-13).Methods:The model described herein is a Markov cohort model built to simulate the epidemiological burden of pneumococcal- and NTHi-related diseases within birth cohorts in the UK and Canada. Base-case assumptions include estimates of vaccine efficacy and NTHi infection rates that are based on published literature.Results:The model predicts that the two vaccines will provide a broadly similar impact on all-cause invasive disease and CAP under base-case assumptions. However, PHiD-CV is expected to provide a substantially greater reduction in AOM compared with PCV-13, offering additional savings of Canadian $9.0 million and £4.9 million in discounted direct medical costs in Canada and the UK, respectively.Limitations:The main limitations of the study are the difficulties in modelling indirect vaccine effects (herd effect and serotype replacement), the absence of PHiD-CV- and PCV-13-specific efficacy data and a lack of comprehensive NTHi surveillance data. Additional limitations relate to the fact that the transmission dynamics of pneumococcal serotypes have not been modelled, nor has antibiotic resistance been accounted for in this paper.Conclusion:This cost-effectiveness analysis suggests that, in Canada and the UK, PHiD-CV’s potential to protect against NTHi infections could provide a greater impact on overall disease burden than the additional serotypes contained in PCV-13.

Estimating the age-specific duration of herpes zoster vaccine protection: A matter of model choice?

IntroductionThe estimation of herpes zoster (HZ) vaccine efficacy by time since vaccination and age at vaccination is crucial to assess the effectiveness and cost-effectiveness of HZ vaccination. Published estimates for the duration of protection from the vaccine diverge substantially, although based on data from the same trial for a follow-up period of 5years. Different models were used to obtain these estimates, but it is unclear which of these models is most appropriate (if any). Only one study estimated vaccine efficacy by age at vaccination and time since vaccination combined. Recently, data became available from the same trial for a follow-up period of 7years. Aim and methodsWe aim to elaborate on estimating HZ vaccine efficacy (1) by estimating it as a function of time since vaccination and age at vaccination, (2) by comparing the fits of a range of models, and (3) by fitting these models on data for a follow-up period of 5 and 7years. ResultsAlthough the models’ fit to data are very comparable, they differ substantially in how they estimate vaccine efficacy to change as a function of time since vaccination and age at vaccination. DiscussionAn accurate estimation of HZ vaccine efficacy by time since vaccination and age at vaccination is hampered by the lack of insight in the biological processes underlying HZ vaccine protection, and by the fact that such data are currently not available in sufficient detail. Uncertainty about the choice of model to estimate this important parameter should be acknowledged in cost-effectiveness analyses.

Less Is More: A Step in the Right Direction for Human Papillomavirus (HPV) Vaccine Implementation

Although immunization with two highly efficacious human papillomavirus (HPV) vaccines holds great promise for reducing the global burden of HPV-related cancers, the barriers to achieving this goal remain substantial. The cost of HPV vaccination still represents an important obstacle to implementation in many countries but there are several challenges beyond the high cost (1). It has proven difficult to achieve high levels of coverage with all three HPV vaccine doses even in countries with considerable resources. In the United States, where HPV vaccine delivery is principally by primary care physicians, the uptake of the complete three-dose series of HPV vaccine was recently estimated at 32% among 13- to 17-year-old girls (2). This low rate of series completion contrasts with the outstanding successes in Australia and the United Kingdom where school-based HPV vaccine programs have achieved much higher rates of coverage for the third HPV vaccine dose (≥72% and ≥84%, respectively) in the primary target population of 12- and 13-year-old girls (3,4). Functional and routine preventive health-care platforms are nearly nonexistent for adolescents worldwide, therefore school-based immunization programs, where feasible, can provide a solution to achieving high vaccine coverage. Beyond providing a venue for adolescent immunization, evidence from England (4) suggests that school-based HPV vaccine delivery can achieve equity in coverage of 12-year-old girls across deprivation levels of the areas where they live. In the United States, HPV vaccination rates have been strongly and inversely correlated with cervical cancer mortality rates and median income (5). Because cervical screening coverage is inversely associated with poverty and deprivation (6), ensuring equitable HPV vaccine delivery and high coverage in populations that are less likely to have opportunities for cervical screening as adults remains a priority. In addition to problems associated with the cost and organizational challenges of HPV vaccine delivery, there has been little to no information available to examine potential alternative immunization schedules or the efficacy of HPV vaccination with less than the recommended full three-dose series. Sustained immunogenicity and immune memory has been demonstrated following administration of two doses of the hepatitis B vaccine (7), and preliminary data on HPV-specific antibody titers have suggested that two HPV vaccine doses may be equivalent to three (8). However, experts have speculated that a single dose of the HPV vaccine, like other recombinant subunit vaccines, is unlikely to be efficacious. In this issue of the Journal, Kreimer et al. (9) present the first clinical evidence to support the efficacy of fewer than three doses of the bivalent HPV16/18 vaccine. The Costa Rica Vaccine Trial, in which this study was nested, was not specifically designed to measure vaccine efficacy (VE) when less than the complete threedose HPV vaccine series was delivered. Thus, the main reasons that participants in this analysis did not receive three doses were involuntary, including pregnancy and colposcopy referral; few participants refused vaccination. After a median follow-up time of 4.2 years, two doses of the bivalent HPV vaccine demonstrated high VE against incident HPV16 and HPV18 infections that persisted for at least 1 year (VE = 84.1%, 95% confidence interval [CI] = 50.2% to 96.3%), and even a single dose was highly efficacious (VE =100%, 95% CI = 66.5% to 100%). The VE for two and three doses was essentially the same. Importantly, the VE estimates are supported by similar attack rates of incident HPV16 or HPV18 infections that persisted for 1 year among women who received one dose (5.3%), two doses (4.5%), or three doses (4.4%), indicating that they were at similar risk for acquiring HPV infections regardless of the number of doses. Cross-protection against the composite endpoint of incident 1-year persistent infection by HPV31, HPV33, and HPV45 has been reported previously (10) for women who received the standard three-dose regimen of the bivalent HPV vaccine (VE = 41.3%, 95% CI = 18.9% to 57.9%). Kreimer et al. (9), however, show no evidence of vaccine cross-protection in women who received two doses of the HPV16/18 vaccine (VE = 225.9%, 95% CI = 2334% to 61.1%), and although the data are limited, they do suggest that

Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: Comparing estimates for 7-valent, 10-valent, and 13-valent vaccines

IntroductionAlthough multiple studies of cost-effectiveness of pneumococcal conjugate vaccines have been conducted, no such study has examined Singapore's situation nor compared the licensed conjugate vaccines in an Asian population. This paper estimates the costs and public health impacts of pneumococcal conjugate vaccine programs, varying estimates of serotype replacement and herd immunity effects as key parameters in the analysis. Based in part on a 2008 analysis also presented here, Singapore has approved the PCV-7, PHiD-10, and PCV-13 pneumococcal conjugate vaccines as part of its National Childhood Immunisation Programme. MethodsAn economic evaluation was performed using a Markov simulation model populated with Singapore-specific population parameters, vaccine costs, treatment costs, and disease incidence data. The vaccinated infant and child cohort of 226,000 was 6% of the Singapore resident population of 3.8 million. Vaccine efficacy estimates were constructed for PCV-7, PHiD-10, and PCV-13 vaccines based on their serotype coverage in Singapore and compared to ‘no vaccination’. The model estimated impacts over a five-year time horizon with 3% per year discounting of costs and health effects. Costs were presented in 2010 U.S. dollars (USD) and Singapore dollars (SGD). Sensitivity analyses included varying herd immunity, serotype replacement rates, vaccine cost, and efficacy against acute otitis media. ResultsUnder base case assumptions for the revised analysis (i.e., herd effects in the unvaccinated population equivalent to 20% of direct effects) PCV-13 prevented 834 cases and 7 deaths due to pneumonia, meningitis, and bacteremia in the vaccinated population, and 952 cases and 191 deaths in the unvaccinated population over the 5-year time horizon. Including herd effects, the cost-effectiveness ratio for PCV-13 was USD $37,644 (SGD $51,854) per QALY. Without herd effects, however, the ratio was USD $204,535 (SGD $281,743) per QALY. The PCV-7 cost per QALY including herd effects was USD $43,275 (SGD $59,610) and for PHiD-10 the ratios were USD $45,100 (SGD $62,125). The original 2008 analysis, which had higher estimates of pneumonia prevention due to herd immunity and lower estimates of cost per dose, had found a cost-effectiveness ratio of USD $5562 (SGD $7661) per QALY for PCV-7. ConclusionsWhen compared to cost-effectiveness thresholds recommended by the World Health Organization (WHO), our 2008 analysis found that vaccination of infants in Singapore with PCV-7 was very cost-effective if herd immunity effects were present. However, knowledge on herd immunity and serotype replacement that emerged subsequent to this analysis changed our expectations about indirect effects. Given these changed inputs, our current estimates of infant vaccination against pneumococcal disease in Singapore find such programs to be moderately cost-effective compared to WHO thresholds. The different findings from the 2008 and 2011 analyses suggest that the dynamic issue of serotype replacement should be monitored post-licensure and, as changes occur, vaccine effectiveness and cost-effectiveness analyses should be re-evaluated.

Improved Detection of Nasopharyngeal Cocolonization by Multiple Pneumococcal Serotypes by Use of Latex Agglutination or Molecular Serotyping by Microarray

Identification of Streptococcus pneumoniae in the nasopharynx is critical for an understanding of transmission, estimates of vaccine efficacy, and possible replacement disease. Conventional nasopharyngeal swab (NPS) culture and serotyping (the WHO protocol) is likely to underestimate multiple-serotype carriage. We compared the WHO protocol with methods aimed at improving cocolonization detection. One hundred twenty-five NPSs from an infant pneumococcal-carriage study, containing ≥ 1 serotype by WHO culture, were recultured in duplicate. A sweep of colonies from one plate culture was serotyped by latex agglutination. DNA extracted from the second plate was analyzed by S. pneumoniae molecular-serotyping microarray. Multiple serotypes were detected in 11.2% of the swabs by WHO culture, 43.2% by sweep serotyping, and 48.8% by microarray. Sweep and microarray were more likely to detect multiple serotypes than WHO culture (P < 0.0001). Cocolonization detection rates were similar between microarray and sweep, but the microarray identified the greatest number of serotypes. A common serogroup type was identified in 95.2% of swabs by all methods. WHO methodology significantly underestimates multiple-serotype carriage compared to these alternate methods. Sweep serotyping is cost-effective and field deployable but may fail to detect serotypes at low abundance, whereas microarray serotyping is more costly and technology dependent but may detect these additional minor carried serotypes.

Endemic diphtheria in Ho Chi Minh City; Viet Nam: A matched case–control study to identify risk factors of incidence

From 1999 to 2004, Ho Chi Minh City (HCMC), Vie Nam reported 401 clinically suspected and 90 laboratory-confirmed diphtheria . To identify risk factors, a matched case–control study was conducted during 2005 and 2006. In total, 88 cases that occurred in 2003 and 2004 and 352 age- and sex-matched controls were studied. No DPT/DT immunisation (odds ratio, 9.9 [95% CI, 1.9–52.3]) and bathing only once a day or less (OR 1.7 [95% CI, 1.0–2.9]) were associated with diphtheria incidence. Estimated vaccine efficacy of three or more DPT/DT doses was 88%. Immunising children with zero-dose status of diphtheria toxoid inoculation, rather than the introduction of booster doses, and the promotion of skin hygiene were considered to be the priority interventions in controlling the endemic diphtheria in HCMC.

A new approach to estimate vaccine efficacy based on immunogenicity data applied to influenza vaccines administered by the intradermal or intramuscular routes

BackgroundDespite their pivotal role in the assessment of influenza vaccines, limited attempts have been made to use hemagglutination inhibition (HI) titers for predicting vaccine efficacy against laboratory-confirmed influenza. We present here the second step of a two-step approach allowing performing such predictions and use it to compare a new trivalent inactivated influenza vaccine administered by the intradermal (ID) route (INTANZA®/IDFlU®) with the vaccine administered by the classical intramuscular (IM) route.ResultsPooling all available immunogenicity data, the predicted vaccine efficacy was 63.3% [CI: 58.1; 68.7] for ID route and 54.4% [CI: 49.4; 59.2] for IM route. The corresponding relative increase in efficacy was 16.5% [CI: 12.7; 20.1]. Predicted vaccine efficacies decreased with age for both vaccines, but the decrease was less marked by ID route: the relative increase in efficacy for subjects aged 70 years and above is of 18.0% [CI:12;24]:MethodsThe first step corresponding to the estimation of the level of protection against laboratory-confirmed influenza that can be linked to each HI titer, referred to as the HI protection curve, was achieved by using a meta-analytical approach based on published information. Vaccine efficacy and differences in vaccine efficacy are predicted in a second step using this HI protection curve alongside the results of two randomized clinical trials providing comparative information on the immunogenicity of trivalent inactivated influenza vaccines administered ID or IM in 3,503 & 1,645 elderly participants, respectively.ConclusionThe analysis performed confirmed that the superior immune response provided by the vaccine using the ID route should translate into a higher vaccine efficacy against laboratory-confirmed influenza.

The Cost‐Effectiveness of Rotavirus Vaccination in Malawi

Rotarix (GlaxoSmithKline), a newly licensed rotavirus vaccine requiring 2 doses, may have the potential to save hundreds of thousands of lives in Africa. Nations such as Malawi, where Rotarix is currently under phase III investigation, may nevertheless face difficult economic choices in considering vaccine adoption. The cost-effectiveness of implementing a Rotarix vaccine program in Malawi was estimated using published estimates of rotavirus burden, vaccine efficacy, and health care utilization and costs. With 49.5% vaccine efficacy, a Rotarix program could avert 2582 deaths annually. With GAVI Alliance cofinancing, adoption of Rotarix would be associated with a cost of $5.07 per disability-adjusted life-year averted. With market pricing, Rotarix would be associated with a base case cost of $74.73 per disability-adjusted life-year averted. Key variables influencing results were vaccine efficacy, under-2 rotavirus mortality, and program cost of administering each dose. Adopting Rotarix would likely be highly cost-effective for Malawi, particularly with GAVI support. This finding holds true across uncertainty ranges for key variables, including efficacy, for which data are becoming available.

Efficacy of HPV 16/18 vaccines on sexually active young women and the impact on organized cervical cancer screening

Sir, We read with interest the paper by Sigurdsson and colleagues recently published in AOGS (1). They cleverly integrated different data to answer some of the most urgent questions about screening in the vaccine era and about efficacy of the vaccine in sexually active women. Most of their deductive conclusions are sound. However, in our opinion two points need deeper insight: (1) the lower age limit for screening in vaccinated cohorts, and (2) the effect of the length of follow-up on the estimates of vaccine efficacy in a young sexually active population of unknown HPV infection status. On point (1), the authors state that the reduction of CIN2+ in younger women is similar to (and not greater than) that in older women. Therefore, they suggest not raising the lower age limit for screening. Actually, screening programs are there for the interest in preventing invasive cancers, rather than CIN2 or CIN3, particularly in younger women whose probability of regression is very high. In public health, in fact, we are more interested in absolute risk than relative measures: even if the relative proportion of 16/18 HPV vs. non-16/18 cancer is the same in younger and older women, the absolute risk of non-16/18 in the former is extremely low. Consequently, in a vaccinated population, the lower age limit for screening should not be modified if the predicted number of cases not prevented through vaccination in 22–29–year-old women justifies a mass screening in that age group. On point (2) we ask: Is it safe to quantify the impact of a vaccine on a sexually active population using the results of a trial with a short follow-up? It is well established that the median time from infection to CIN3 is quite long (2, 3). If we look at the intention-to-treat efficacy results in the FUTURE-II study, we note that most lesions in the placebo group were due to infections already present at enrollment (4). Since the vaccine has no therapeutic effect (5), the baseline prevalence of infection and of disease in the vaccination group is similar. The final effect dilutes the vaccine's efficacy. As time passes, the proportion of lesions due to newly acquired infections increases, accentuating the differences between placebo and vaccination groups, which maintains the vaccine's efficacy. To quantify this effect we have to rely on some parameters of the natural progression of the disease, namely the length of the latency period from infection to disease and the age-specific transition probabilities, i.e. the probability of infection, of progression from infection to high-grade lesions, and then to cancer. Figure 1 shows that shorter latency times and lower variances mean greater vaccine efficacy in sexually active women at longer follow-up, and vice versa. The graph A shows the proportion of prevented cases and estimates of efficacy at two different follow-up times under a given latency time; graph B and C, respectively, show the effects of a reduction in latency time and an increase in latency variance.

Estimation of measles vaccine efficacy and critical vaccination coverage in a highly vaccinated population

Measles is a highly infectious disease that has been targeted for elimination from four WHO regions. Whether and under which conditions this goal is feasible is, however, uncertain since outbreaks have been documented in populations with high vaccination coverage (more than 90%). Here, we use the example of a large outbreak in a German public school to show how estimates of key epidemiological parameters such as the basic reproduction number (R(0)), vaccine efficacy (VE(S)) and critical vaccination coverage (p(c)) can be obtained from partially observed outbreaks in highly vaccinated populations. Our analyses rely on Bayesian methods of inference based on the final size distribution of outbreak size, and use data which are easily collected. For the German public school the analyses indicate that the basic reproduction number of measles is higher than previously thought (R(0) = 30.8, 95% credible interval: 23.6-40.4), that the vaccine is highly effective in preventing infection (VE(S) = 0.997, 95% credible interval: 0.993-0.999), and that a vaccination coverage in excess of 95 per cent may be necessary to achieve herd immunity (p(c) = 0.971, 95% credible interval: 0.961-0.978). We discuss the implications for measles elimination from highly vaccinated populations.

Modelling the Transmission Dynamics and Control of the Novel 2009 Swine Influenza (H1N1) Pandemic

The paper presents a deterministic compartmental model for the transmission dynamics of swine influenza (H1N1) pandemic in a population in the presence of an imperfect vaccine and use of drug therapy for confirmed cases. Rigorous analysis of the model, which stratifies the infected population in terms of their risk of developing severe illness, reveals that it exhibits a vaccine-induced backward bifurcation when the associated reproduction number is less than unity. The epidemiological consequence of this result is that the effective control of H1N1, when the reproduction number is less than unity, in the population would then be dependent on the initial sizes of the subpopulations of the model. For the case where the vaccine is perfect, it is shown that having the reproduction number less than unity is necessary and sufficient for effective control of H1N1 in the population (in such a case, the associated disease-free equilibrium is globally asymptotically stable). The model has a unique endemic equilibrium when the reproduction number exceeds unity. Numerical simulations of the model, using data relevant to the province of Manitoba, Canada, show that it reasonably mimics the observed H1N1 pandemic data for Manitoba during the first (Spring) wave of the pandemic. Further, it is shown that the timely implementation of a mass vaccination program together with the size of the Manitoban population that have preexisting infection-acquired immunity (from the first wave) are crucial to the magnitude of the expected burden of disease associated with the second wave of the H1N1 pandemic. With an estimated vaccine efficacy of approximately 80%, it is projected that at least 60% of Manitobans need to be vaccinated in order for the effective control or elimination of the H1N1 pandemic in the province to be feasible. Finally, it is shown that the burden of the second wave of H1N1 is expected to be at least three times that of the first wave, and that the second wave would last until the end of January or early February, 2010.

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

BackgroundPhase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa. Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.MethodsTheoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.ResultsHeterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting. This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored. Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.ConclusionsFailure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy. Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.

Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A?

BackgroundIntroduction of the 7-valent pneumococcal conjugate vaccine (7vCRM) in several countries has led to a rapid, significant drop in vaccine-type invasive pneumococcal disease (IPD) in immunized children. In the United States and some other countries with high antibiotic use, a subsequent rise in serotype 19A IPD has been taken to indicate that the 19F conjugate in the vaccine provides no cross-protection against the immunologically related 19A.DiscussionWe systematically assessed the clinical efficacy and effectiveness of 19F-containing vaccines against 19A disease or nasopharyngeal carriage by searching English-language articles in the electronic databases PubMed, Current contents, Scopus, and Embase from 1985 to 2008. The vaccine efficacy and effectiveness point estimates were consistently positive for modest protection against 19A IPD and acute otitis media (AOM). However, statistical significance was not reached in any individual study. No consistent impact of 7vCRM on 19A nasopharyngeal colonization could be detected. These findings are discussed in context of immunogenicity analyses indicating that 7vCRM induces functionally active anti-19A antibodies after the booster dose, and that other 19F-containing vaccine formulations may elicit higher levels of such antibodies after both primary and booster doses.SummaryTaken together, these results suggest that 19F-conjugates can provide some protection against 19A disease. The magnitude of this protection in a given setting will likely depend on several factors. These include the anti-19A immunogenicity of the specific vaccine formulation, the number of doses of that formulation needed to elicit the response, and the burden of 19A disease that occurs after those doses. It is possible that a modest protective effect may be obscured by the presence of countervailing selection pressures (such as high antibiotic use) that favor an increase in colonization with antibiotic-non-susceptible strains of 19A.

TUBERCULOSIS IN EUROPEAN BADGERS (MELES MELES) AND THE CONTROL OF INFECTION WITH BACILLE CALMETTE-GUÉRIN VACCINATION

The eradication of tuberculosis (Mycobacterium bovis infection) from cattle herds may be compromised if infected wildlife species, such as European badgers (Meles meles), share the same environment and contribute to transfer of infection. Options for dealing with tuberculosis in this wild reservoir host are limited by conservation and social concerns, despite a clear implication that infected badgers are involved with the initiation of tuberculosis in cattle herds. Vaccination of badgers against M. bovis, if successfully employed, would directly facilitate the completion of bovine tuberculosis eradication in affected areas. Vaccine trials in captive badgers have established that the M. bovis bacille Calmette-Guérin (BCG) vaccine can induce a protective response that limits the distribution and severity of tuberculosis disease following experimental challenge. The protective effect of the vaccine has been demonstrated when the vaccine was delivered by subcutaneous injection, deposited on mucous membranes, and given orally in a lipid formulation. A large-scale field trial of oral BCG vaccine has been designed to measure the protection generated in wild badgers subjected to natural transmission of infection and to estimate vaccine efficacy. These parameters will be estimated by comparing the prevalence of M. bovis infection in vaccinated and nonvaccinated badgers. The results will provide a framework for the development and implementation of a national strategy to eliminate the disease in badger populations and if successful will remove this major impediment to bovine tuberculosis eradication.

Escherichia coliO157:H7 Vaccine Dose–Effect in Feedlot Cattle

A clinical trial conducted during the summer of 2006 evaluated effects of two- and three-dose regimens of an Escherichia coli O157 vaccine product on the probability of detecting E. coli O157:H7 in feces and colonization of the terminal rectum. The three-dose regimen significantly reduced the probability for cattle to shed E. coli O157:H7 in feces 65% compared to placebo-treated cattle. A dose-effect was demonstrated because a two-dose regimen of the vaccine product was intermediate in effect. These results are consistent with previous estimates of vaccine efficacy against fecal shedding, and agree with our previous finding that efficacy of two or three doses of this vaccine product exhibit a dose-response.

Rotavirus and the Indigenous Children of the Australian Outback: Monovalent Vaccine Effective in a High‐Burden Setting

Indigenous children living in arid Central Australia experience frequent outbreaks of rotavirus gastroenteritis. A widespread outbreak of G9 rotavirus infection occurred several months after introduction of the RIX4414 rotavirus vaccine. We performed a retrospective case-control study to determine vaccine efficacy during the outbreak. Two doses provided an estimated vaccine efficacy of 77.7% (95% confidence interval, 40.2%-91.7%) against hospitalization for gastroenteritis. Vaccine efficacy was 84.5% (95% confidence interval, 23.4%-96.9%) against confirmed cases of rotavirus infection. Vaccination was effective in this high-burden setting.