Vaccinations in Primary Care.

Vaccination is amongst the best strategies to improve child survival and reduce morbidity. Vaccines represent the most cost effective and simple intervention to protect against distressing epidemics. There are mortality and morbidity related benefits derived from preventing infectious diseases through vaccination; these include financial benefits by avoiding hospitalization, preventing long-term disability and increased productivity. Ever since the invention of the first vaccine against smallpox by Edward Jenner in 1796, vaccination has become indispensable healthcare intervention and has saved millions of lives. Due to significant scientific progress, many vaccines are available and numerous are anticipated; however, vaccine preventable infectious diseases are still prevalent. Due to rapid pace of developments in the field of vaccination, providers must continue to update their knowledge. The present review is aimed at helping general practitioners understand routine vaccinations, their considerations, issues and side effects.

A Proposal to Redefine Clinical Immunogenicity Assessment.

With more than 100 therapeutic proteins (TP) approved since the first EMA guidance on immunogenicity in 2007, a vast amount of clinical experience with a variety of therapeutic proteins has been gained. This has provided data on anti-drug antibodies (ADA) and their observed clinical impact, or lack thereof. It has become evident that not all ADA responses are clinically relevant. The current "standard practice" is to test for ADA in all patients on every study. It is essential that we acknowledge the immunogenicity data gained from marketed TPs and that options for immunogenicity testing reflect this information. Improvements in bioanalytical support throughout the drug development process will eliminate extraneous, non-impactful practices. We propose that low-risk therapeutic proteins could be supported with an event-driven ("collect-and-hold") immunogenicity testing strategy throughout early phases of the clinical program. In the absence of an event, only pivotal studies (where ADA incidence and impact can be decisively assessed) would include default ADA testing. In keeping with the "standard practice," immunogenicity risk assessment must be an on-going and real-time evaluation. This approach has the potential to deliver meaningful, clinically relevant immunogenicity results while maintaining an emphasis on patient safety.

Combining vitamin A and vaccines: convenience or conflict?

The present thesis is based on 11 papers from 1995-2010. The studies have mainly taken place at the Bandim Health Project in Guinea-Bissau, West Africa, but a reanalysis of a randomised trial from Ghana is also included. My research has explored the consequences of combining high-dose vitamin A supplementation and childhood vaccines. Vitamin A deficiency is associated with increased mortality. To protect against the consequences of vitamin A deficiency the World Health Organization recommends that high-dose vitamin A supplements be given together with routine vaccines to children between 6 months and 5 years of age in more than 100 low-income countries. The recommendation is based on logistical considerations. The consequences of combining vitamin A and vaccines were not investigated in randomised trials prior to the implementation of this policy - it was assumed that the interventions were independent. My first project aimed to study the effect on the immune response to measles of providing vitamin A together with measles vaccine. We found that the two interventions were not independent. Vitamin A enhanced the antibody response to measles vaccine given at 9 months of age significantly, especially in boys. The effects were sustained over time; the children who had received vitamin A with their measles vaccine were more protected against measles at 6-8 years of age. Though vitamin A supplementation had a beneficial effect on the immune response to measles vaccine, it intrigued me that the effect of vitamin A supplementation on overall mortality was not always beneficial. While vitamin A was beneficial when given after 6 months of age, and two studies had shown a beneficial effect when given at birth, all studies testing the effect between 1-5 months of age had found no effect. These time windows are dominated by three different childhood vaccines: BCG vaccine given at birth, diphtheria-tetanus-pertussis (DTP) vaccine given between 1-5 months of age, and measles vaccine given at 9 months of age. These vaccines have been shown to have strong effects on mortality from infectious diseases in general, so-called non-specific effects. The live BCG and measles vaccine protects against more mortality than can be ascribed to the prevention of tuberculosis and measles, respectively. The inactivated DTP vaccine worryingly has been associated with increased mortality from other infectious diseases. Both positive and negative effects are strongest for girls. I proposed the hypothesis that vitamin A amplifies not only the specific vaccine effects, as we saw for measles vaccine, but also the non-specific effects of vaccines on mortality from other infectious diseases. According to my hypothesis, vitamin A would enhance the non-specific beneficial effects on mortality of BCG and measles vaccine, but also the negative effects of DTP vaccine. Hence, the hypothesis offered an explanation for the mortality-age pattern after vitamin A supplementation. Since it was formulated, I have aimed to test this hypothesis. Since it is associated with ethical problems to randomise children above 6 months of age to vitamin A supplementation, and to randomise children in general to recommended vaccines, we have had to be pragmatic when designing the trials. Hence, our studies have taken many different forms. We conducted an observational study during a vitamin A campaign in which missing vaccines were also provided, and a randomised trial testing the effect of two different doses of vitamin A during another campaign; we tested the effect of providing vitamin A with BCG at birth in two randomised trials, and we reanalysed data from one of the original randomised trials of vitamin A supplementation from the perspective of vaccination status. In all studies the main outcome was mortality. The results document that vitamin A supplements do more than protect against vitamin A deficiency. They support the hypothesis that vitamin A supplements interact with vaccines with important consequences for mortality. First, a smaller dose of vitamin A was more beneficial than a larger dose for girls. Second, the effect of vitamin A given with DTP vaccine was significantly different from the effect of vitamin A given with measles vaccine, and children, who received vitamin A with DTP vaccine, had higher mortality than children, who had received vitamin A alone, or who did not receive anything. Third, vitamin A given with BCG at birth interacted negatively with subsequent DTP vaccines in girls. Fourth, the effect of vitamin A to older children in Ghana depended on vaccination status, being beneficial in boys, but harmful in girls who received DTP vaccine during follow-up. The results also show that boys and girls respond differently to vitamin A and vaccines. It is a common assumption within public health in low-income countries that interventions can be combined without producing unexpected consequences. The work presented in this thesis confronts this assumption; the results show that vitamin A and vaccines should be seen not only as specific interventions with specific and independent effects, but as immuno-modulators, which can interact with important consequences for overall mortality. Combining interventions can be convenient and lead to synergistic health benefits, but we documented several examples, where it also leads to unexpectedly increased mortality. Thus, to optimise the child health intervention policy in low-income countries a shift in paradigm is needed. Health interventions should no longer be seen as merely specific and independent, and the policy should probably not be the same for boys and girls. Though more complex, it is necessary to evaluate all health interventions in terms of their effect on overall mortality - and their potential interactions with other health interventions and potential sex-differential effects should always be investigated. Only in this way can we assure that the children in the poorest countries get the best possible treatment and avoid using large amounts of money and resources on interventions which may, in worst case, kill them.

Human papillomavirus vaccination in the prevention of cervical neoplasia.

Cervical cancer remains a major cause of morbidity and mortality for women worldwide. Although the introduction of comprehensive screening programs has reduced the disease incidence in developed countries, it remains a major problem in the developing world. The recent licensing of 2 vaccines against human papillomavirus (HPV) type 16 and HPV-18, the viruses responsible for 70% of cervical cancer cases, offers the hope of disease prevention. In this article, we review the role of HPV in the etiology of cervical cancer and the evidence to support the introduction of vaccination programs in young women and discuss the potential obstacles to widespread vaccination. In addition, we discuss the issues that remain to be elucidated, including the potential need for booster doses of the vaccine and the role of concomitant vaccination in men.

Fish immunity and parasite infections: from innate immunity to immunoprophylactic prospects.

The increasing economic importance of fish parasitoses for aquaculture and fisheries has enhanced the interest in the defence mechanisms against these infections. Both innate and adaptive immune responses are mounted by fish to control parasite infections, and several mechanisms described for mammalian parasitoses have also been demonstrated in teleosts. Innate immune initiation relies on the recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognizing receptors (PRRs). A number of PRRs, mainly Toll-like receptors (TLRs), have been characterized in fish, and some molecules susceptible of functioning as PAMPs are known for some fish parasites. A lectin-carbohydrate interaction has also been described in some host fish-parasite systems, thus probably involving C-type lectin receptors. Inflammatory reactions involving cellular reactions, as phagocytosis and phagocyte activity (including oxidative mechanisms), as well as complement activity, are modulated by many fish parasites, including mainly ciliates, flagellates and myxozoans. Besides complement, a number of humoral immune factors (peroxidases, lysozyme, acute-phase proteins) are also implicated in the response to some parasites. Among adaptive responses, most data deal with the presence of B lymphocytes and the production of specific antibodies (Abs). Although an increasing number of T-cell markers have been described for teleosts, the specific characterization of those involved in their response is far from being obtained. Gene expression studies have demonstrated the involvement of other mediators of the innate and adaptive responses, i.e., cytokines [interleukins (IL-1, IL-8), tumor necrosis factor (TNF), interferon (IFN)], chemokines (CXC, CC), as well as several oxidative enzymes [inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX-2)]. Information is scarcer for factors more directly linked to adaptive responses, such as major histocompatibility (MH) receptors, T cell receptors (TCRs) and IgM. Expression of some immune genes varied according to the phase of infection, and proinflammatory cytokines were mainly activated in the early stages. Gene expression was generally higher in the target tissues for some skin and gill parasites, as Ichthyophthirius multifiliis, Neoparamoeba spp. and Lepeophtheirus salmonis, thus confirming the relevance of mucosal immunity in these infections. The existence of protective responses has been demonstrated for several fish parasites, both in natural infections and in immunization studies. Most information on the mechanisms involved in protection deals with the production of specific Abs. Nevertheless, their levels are not always correlated to protection, and the precise involvement of immune mechanisms in the response is unknown in many cases. No commercial vaccine is currently available for piscine parasitoses, although experimental vaccines have been assayed against I. multifiliis, Cryptobia salmositica and scuticociliates. The known information points to the need for integrated studies of the mechanisms involved in protection, in order to choose the optimum antigen candidates, adjuvants and formulations.

Long-term immunity to hepatitis B among a sample of fully vaccinated children in Cairo, Egypt.

We assessed the long-term immunity to hepatitis B among 242 Egyptian children aged 6-12 years who had received a full vaccination course in infancy, and investigated the factors associated with immunity. Only 39.4% of the children had protective (> or = 10 lU/L) hepatitis B surface antibody levels (HBsAb). This proportion decreased with age but the decrease was not statistically significant. The mean level of HBsAb decreased significantly with increasing age (P = 0.026). A significant negative correlation was found between current age and HBsAb levels (r = -0.31, P = 0.041). Age and weight-for-age were found to be significant predictors of non-protective HBsAb levels.

Residual susceptibility to measles among young adults in Victoria, Australia following a national targeted measles-mumps-rubella vaccination campaign.

BACKGROUND: Past measles immunisation policies in Australia have resulted in a cohort of young adults who have been inadequately vaccinated, but who also have low levels of naturally acquired immunity because immunisation programs have decreased the circulation of wild virus. A measles-mumps-rubella (MMR) immunisation campaign aimed at addressing this susceptibility to measles among young adults was conducted in Australia in 2001-2. By estimating age-specific immunity, we aimed to evaluate the success of this campaign in the state of Victoria. METHODS: We conducted serosurveys after the young adult MMR program at state and national levels to estimate immunity among young adults born between 1968-82. We compared results of the Victorian (state) surveys with the Victorian component of the national surveys and compared both surveys with surveys conducted before the campaign. We also reviewed all laboratory confirmed measles cases in Victoria between 2000-4. RESULTS: The Victorian state serosurveys indicated no significant change in immunity of the cohort following the young adult MMR campaign (83.9% immune pre and 85.5% immune post campaign) while the Victorian component of the national serosurvey indicated a significant decline in immunity (91.0% to 84.2%; p = 0.006). Both surveys indicated about 15% susceptibility to measles among young Victorian adults after the campaign. Measles outbreaks in Victoria between 2000-4 confirmed the susceptibility of young adults. Outbreaks involved a median of 2.5 cases with a median age of 24.5 years. CONCLUSION: In Victoria, the young adult MMR program appears to have had no effect on residual susceptibility to measles among the 1968-82 birth cohort. Young adults in Victoria, as in other countries where past immunisation policies have left a residual susceptible cohort, represent a potential problem for the maintenance of measles elimination.

Stochastic simulation and the detection of immunity to schistosome infections.

In this paper we address the question of detecting immunity to helminth infections from patterns of infection in endemic communities. We use stochastic simulations to investigate whether it would be possible to detect patterns predicted by theoretical models, using typical field data. Thus, our technique is to simulate a theoretical model, to generate the data that would be obtained in field surveys and then to analyse these data using methods usually employed for field data. The general behaviour of the model, and in particular the levels of variability of egg counts predicted, show that the model is capturing most of the variability present in field data. However, analysis of the data in detail suggests that detection of immunity patterns in real data may be very difficult even if the underlying patterns are present. Analysis of a real data set does show patterns consistent with acquired immunity and the implications of this are discussed.

Evolution and immunology. The economics of immunity.

Our vigilant immune systems are ready to mount an attack as soon as an invading pathogen is spotted. But what is the cost of keeping this sophisticated defense system on red alert? In a provocative Perspective, Read and Allen discuss new findings showing that the cost of immune defense in animals is very high (Moret and Schmid-Hempel), and the claim that, in some circumstances, the cost may be worth the benefit gained (Nunn et al.).

A stochastic model of schistosomiasis immuno-epidemiology.

Schistosomiasis is a helminth (worm) infection with approximately 200 million people infected worldwide. There is still controversy on whether differing worm burdens between individuals is a result of differing contact rates or of acquired immunity. In this paper, we present a stochastic modelling framework to address these issues. By using appropriate approximations for the higher moments of the joint distributions, differential equations for the means, variances and co-variances of infection and immunity can be obtained. Numerical solutions of these equations to obtain age profiles of the above properties were compared with Monte Carlo simulations of the stochastic process. Simulations showed that the results depended on whether between host heterogeneity was generated by differing contact rates or differing immune responses. Heterogeneity in contact rates produced a highly aggregated distribution of parasites with a large variance/mean ratio. Heterogeneity in the immune response had very little effect on the overall dynamics. This agrees with the predominant field evidence which would suggest that infection is mainly determined by ecology with a smaller contribution of immunity.

Carrier effects on biological activity of amphotericin B.

Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

Epidemiology and prevention of hepatitis A in travelers.

OBJECTIVE: To assess the risk of hepatitis A in international travelers and to recommend preventive measures. DATA SOURCES: Index Medicus, 1974 through 1983; MEDLINE, 1984 through 1993; and unpublished data of the Centers for Disease Control and Prevention. STUDY SELECTION: Review of all retrospective and cohort studies on hepatitis A and other vaccine-preventable diseases in travelers, of seroepidemiologic surveys of hepatitis A virus (HAV) antibodies in travelers, of data on the various hepatitis A vaccines, of economic analyses, and of recommendations of recognized organizations. DATA EXTRACTION: Independent analysis by multiple observers. DATA SYNTHESIS: The incidence rate for unprotected travelers, including those staying in luxury hotels, is estimated to be three per 1000 travelers per month of stay in a developing country. Persons eating and drinking under poor hygienic conditions have a rate of 20/1000 per month. This makes hepatitis A the most frequent infection in travelers that may be prevented by immunization. In many industrialized countries persons born after 1945 have an HAV antibody seroprevalence (immunity) of less than 20%. New inactivated HAV vaccines induce protective antibodies in more than 95% of recipients and offer protection estimated to last for 10 years or more, whereas protection by immune globulin lasts only 3 to 5 months. CONCLUSIONS: Hepatitis A vaccine, or immune globulin where HAV vaccine is not available, is recommended for all nonimmune travelers visiting developing countries. Prescreening for antibodies to HAV in travelers living in countries with low prevalence is usually not necessary in persons born after 1945.

Cost effectiveness of prevaccination screening of health care workers for immunity to measles, rubella and mumps.

OBJECTIVES: To determine the value of infection and vaccination histories as predictors of immunity to measles, rubella and mumps, and to compare the costs of various screening strategies with the cost of universal vaccination of health care workers. SETTING: Staff employed by a Sydney children's hospital. METHODS: Histories of measles, rubella and mumps infection or vaccination were compared with the results of serological testing to determine which historical statements had high positive predictive values (PPV) for immunity. Using this, we devised three prevaccination screening strategies and compared their costs with the cost of universal staff vaccination. RESULTS: Of 235 participants, 98.3% were serologically immune to measles, 96.6% to rubella and 83.0% to mumps. Historical statements indicating immunity with a PPV of more than 95% were histories of measles or of rubella vaccination, and personal recollection of mumps infection. Strategies using historical screening were cheaper than universal vaccination, which in turn was cheaper than using serological screening alone. CONCLUSIONS: Among health care workers at occupational risk of measles, rubella and mumps, the need for vaccination can be reduced by combining historical and serological screening. Where screening is felt to impose an administrative burden, a universal vaccination strategy costs 30%-50% more than strategies which use historical screening.

Comparison of intranasal and aerosol infection of mice in assessment of immunity to influenza virus infection.

A comparison was made of intranasal and aerosol routes of infection with X-31 influenza A virus in Balb/c mice. Mice were first infected with 100 MID50 by either route then challenged 42 days later with the same virus given by the same or alternative route. Three days following each infection, pulmonary virus was measured by inoculation of chick embryos. Mice initially infected under ether anesthesia by intranasal inoculation experienced higher initial mortality but proved most resistant to subsequent challenge by either method. In contrast, mice first infected by aerosol were least resistant to intranasal challenge, as indicated by increased rate of infection and pulmonary virus titers, but, like mice previously infected intranasally, were not reinfected by the aerosol route. Thus, intranasal infection appears to be more effective both in inducing and challenging immunity from infection. These results should be considered in the design of experiments utilizing influenza virus infection of mice as a model system.

1988 New Zealand national immunisation survey: methodology.

In 1985 the Department of Health carried out a survey using a two stage stratified random sampling technique to select approximately 3000 children (made up of equal numbers of 5, 10 and 15 year olds). The principal aim was to provide a random sample of sera which could be used or stored for the future to evaluate the national immunisation programme and for screening of an ethical nature. The sampling frame was the 1983 list of public and private schools as provided by the Department of Education. Ninety primary schools and 50 secondary schools were identified, from which 3688 children were asked to participate. There was a 79% consent response rate. The survey largely succeeded in its objective of providing a nationally representative group of children, although the response rate was lower in 5 year olds (74%), in Pacific Islanders (67%), in children from upper socioeconomic status groups (75%), and in children who were reported not to have been immunised (56%). A similar survey is recommended every five years. In the mean time, laboratory analysis of the collected serum samples continues and results will be published separately.