Introduction Vaccination has greatly reduced the burden of infectious diseases. Only clean water, also considered to be a basic human right, performs better. (1) Paradoxically, a vociferous antivaccine lobby thrives today in spite of the undeniable success of vaccination programmes against formerly fearsome diseases that are now rare in developed countries. (2) Understandably, safety gets more public attention than vaccination effectiveness, but independent experts and WHO have shown that vaccines are far safer than therapeutic medicines. (2,3) Modern research has spurred the development of less reactogenic products, such as acellular pertussis vaccines and rabies vaccines produced in cell culture. Today, vaccines have an excellent safety record and most vaccine scares have been shown to be false alarms. (4,5) Misguided safety concerns in some countries have led to a fall in vaccination coverage, causing the re-emergence of pertussis and measles. (6) Putative safety issues are commonly reported while reviews of are few. A Medline search over the past five years using the keywords vaccine risks scored approximately five times as many hits (2655 versus 557) as a Medline search using vaccine benefits as keywords. (7) This reflects the fact that negative aspects of vaccination get much more publicity than positive aspects. How one addresses the antivaccine movement has been a problem since the time of Jenner. The best way in the long term is to refute wrong allegations at the earliest opportunity by providing scientifically valid data. This is easier said than done, because the adversary in this game plays according to rules that are not generally those of science. This issue will not be further addressed in this paper, which aims to show how vaccines are valuable to both individuals and societies, to present validated facts, and to help redress adverse perceptions. Without doubt, vaccines are among the most efficient tools for promoting individual and public health and deserve better press. (8) Disease control Eradication Unless an environmental reservoir exists, an eradicated pathogen cannot reemerge, unless accidentally or malevolently reintroduced by humans, allowing vaccination or other preventive measures to be discontinued. While eradication may be an ideal goal for an immunization programme, to date only smallpox has been eradicated, allowing discontinuation of routine smallpox immunization globally. Potentially, other infectious diseases with no extrahuman reservoir can be eradicated provided an effective and specific diagnostic tests are available. Eradication requires high levels of population immunity in all regions of the world over a prolonged period with adequate surveillance in place. (9) The next disease targeted for eradication is polio, which is still a global challenge. (10) Although high coverage with oral polio (OPV) has eliminated type 2 poliovirus globally, transmission of types 1 and 3 continues in limited areas in a few countries. OPV-caused paralytic disease, directly or by reversion to virulence, and persistent vaccine-virus excretion in immunodeficient individuals are problems yet to be solved. Global use of monovalent type 1 and type 30PV and inactivated polio (IPV) may eventually be required. (10) Elimination Diseases can be eliminated locally without global eradication of the causative microorganism. In four of six WHO regions, substantial progress has been made in measles elimination; transmission no longer occurs indigenously and importation does not result in sustained spread of the virus. (11) Key to this achievement is more than 95% population immunity through a two-dose vaccination regimen. Combined measles, mumps and rubella (MMR) could also eliminate and eventually eradicate rubella and mumps. (11) Increasing measles immunization levels in Africa, where coverage averaged only 67% in 2004, is essential for eradication of this disease. …

In low-income countries, infectious diseases still account for a large proportion of deaths, highlighting health inequities largely caused by economic differences. Vaccination can cut health-care costs and reduce these inequities. Disease control, elimination or eradication can save billions of US dollars for communities and countries, Vaccines have lowered the incidence of hepatocellular carcinoma and will control cervical cancer. Travellers can be protected against "exotic" diseases by appropriate vaccination. Vaccines are considered indispensable against bioterrorism. They can combat resistance to antibiotics in some pathogens. Noncommunicable diseases, such as ischaemic heart disease, could also be reduced by influenza vaccination.Immunization programmes have improved the primary care infrastructure in developing countries, lowered mortality in childhood and empowered women to better plan their families, with consequent health, social and economic benefits.Vaccination helps economic growth everywhere, because of lower morbidity and mortality. The annual return on investment in vaccination has been calculated to be between 12% and 18%. Vaccination leads to increased life expectancy. Long healthy lives are now recognized as a prerequisite for wealth, and wealth promotes health. Vaccines are thus efficient tools to reduce disparities in wealth and inequities in health.

When first introduced in 1992 the hepatitis A vaccine was recommended for individuals at high risk of exposure. This policy was not expected to have a significant impact on disease incidence at population level in view of the epidemiology of the hepatitis A virus (HAV). More recently two countries, Israel and Bahrain, and regions or subpopulations in others (Australia, China, Byelorussia, Italy, Spain, US) have embarked upon more ambitious vaccination programmes that aim to immunize whole birth cohorts. After a brief survey of the virology and epidemiology of HAV, the disease burden it inflicts and a short history of the development of HAV vaccines - both live (in China) and killed vaccines are available - the vaccination programmes introduced in the countries mentioned above are described. The results have been spectacular: disease incidence, not only in the vaccinated cohorts but also in the whole population, have plummeted within a few years of the start of mass vaccination. There is now convincing evidence that the vaccine confers herd immunity if the main spreaders of the virus are targeted for immunization. This finding should encourage other countries to start mass vaccination programmes against HAV, particularly as pharmacoeconomic studies are beginning to show that such a strategy could be a cost-effective way of controlling the disease. It is now even conceivable to eradicate HAV. In fact, this should be easier to achieve than polio eradication as HAV vaccines confer more durable immunity than polio vaccines. However, the global disease burden of HAV is generally thought not to be high enough to justify such an undertaking in the foreseeable future.

Incredibly, vaccines currently capture only about 2% of the world's pharmaceutical market, despite the fact that they can be credited with saving more lives and preventing more suffering and disability than any other form of medical activity, with the possible exception of the provision of clean water.

Polio eradication is within our grasp and, unless something terribly wrong and unexpected happens, the three types of wild polioviruses will cease to circulate in human populations within the next few years. This achievement will be a result of the rational use of OPV. A momentous global decision--discontinuation of vaccination--will then have to be taken. The most important uncertainty that will weigh upon that decision is whether wild polioviruses can re-emerge after "eradication" defined as "complete interruption of wild polioviruses transmission", has been obtained. It is important to realise that "eradication" does not mean "extinction" in the sense that the dodo is extinct. After eradication, wild polioviruses will still lurk in laboratory specimens and in protected environmental sites (like glaciers) and may even "re-emerge" by back mutation or recombination of Sabin-derived strains that may continue to circulate even after OPV use is discontinued. Theoretically, the risk of re-emergence of wild polioviruses would be lessened if IPV was used for a number of years to immunise all those born after cessation of OPV usage. But the question is "by how much?". Vaccination with IPV will reduce the risk that persistent OPV-derived strains (e.g. in immunodeficient patients) will have the chance to establish permanent transmission after vaccination is totally discontinued. However, the risk of re-emergence will not be changed since this will be determined by the risk of accidental re-introduction. Whether the expense of switching completely from OPV to IPV globally can be justified will depend upon the relative risks of wild poliovirus re-emergence from either OPV-derived sources or other environmental sources including "escape" of virulent seed viruses from IPV production facilities. This balance of probabilities and risks will be very difficult to determine. In any case, it is likely that the decision to upscale IPV production to required levels has already been delayed too long so that polio eradication will be achieved by the use of OPV in developed as well as in less developed countries that cannot afford to use IPV at a high enough vaccine coverage rate to make it safe. Wild poLiovirus transmission has been interrupted with OPV in the Western Hemisphere. There is no reason why this cannot be done in the rest of the world. In industrialized countries that can afford it and where vaccine coverage is sufficient to prevent wild virus circulation, IPV, in combined vaccines, will be increasingly used. Let us hope that politicians in developing countries and zealous ethicists in the developed world will understand why, in the present and foreseeable future circumstances, OPV is better than IPV in the poorer countries and will not demand, in the name of equity in health, a total switch to IPV. For eradication, IPV cannot, and hopefully need not, replace OPV. At this stage it should not.

After the publication of case reports of hepatitis B vaccinees with onset or relapse of multiple sclerosis (MS), followed by a media-driven scare campaign in France, the perception that hepatitis B vaccine causes MS has developed. This has led to a fall in the acceptance of hepatitis B vaccination particularly in French-speaking communities which was accelerated by court decisions in favour of vaccination "victims" and the suspension of routine vaccination of pre-adolescents in French schools as a "precautionary measure". This situation has arisen in spite of the absence of scientific data to support a causal link between vaccination and multiple sclerosis. In this article, initially written to inform and reassure employees of one of the vaccine manufacturers, the epidemiological importance of hepatitis B and current knowledge on the aetiology of MS are described. All available data that may throw light on the hypothesis that hepatitis B vaccination is causally linked to MS was reviewed. The conclusion reached on the basis of available data is that the most plausible explanation for the observed temporal association between vaccination and MS is that it is a coincidental association. It is now important to rebuild public confidence in hepatitis B vaccine as well as in vaccination in general.

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.

Journal Article Discussion: Who Should Receive Hepatitis A Vaccine? A Strategy for Controlling Hepatitis A in the United States Get access F. Blaine Hollinger, F. Blaine Hollinger Reprints or correspondence: Dr. F. Blaine Hollinger. Baylor College of Medicine, One Baylor Plaza, Houston. TX 77030. Search for other works by this author on: Oxford Academic PubMed Google Scholar Moderator, Moderator Search for other works by this author on: Oxford Academic PubMed Google Scholar Theodore Eickhoff, Theodore Eickhoff Search for other works by this author on: Oxford Academic PubMed Google Scholar Anne Gershon, Anne Gershon Search for other works by this author on: Oxford Academic PubMed Google Scholar Elaine C. Jong, Elaine C. Jong Search for other works by this author on: Oxford Academic PubMed Google Scholar Raymond S. Koff Raymond S. Koff Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 171, Issue Supplement_1, March 1995, Pages S73–S77, https://doi.org/10.1093/infdis/171.Supplement_1.S73 Published: 01 March 1995

Clinical trials of an inactivated hepatitis A vaccine have encompassed 104 studies completed by December 1993 in 27 countries. Studies involved 50,677 subjects and administration of > 120,000 vaccine doses. Results show that the vaccine is safe, clinically well-tolerated, and highly immunogenic in all age groups. A seroconversion rate of 100% is achieved 1 month after primary vaccination. Vaccine-induced antibody titers persist after a primary vaccination course for > or = 1 year with a single dose of 1440 ELISA units (EL.U.) in adults and after two doses of 360 EL.U. in children. A booster dose 6-12 months after the first vaccine dose induces very high antibody titers, which according to a mathematical model, are expected to protect against hepatitis A for > 20 years. The vaccine is equally immunogenic when administered simultaneously with other traveler vaccines, therefore enabling flexible and convenient vaccination against hepatitis A.

The basis for the development of a vaccine against hepatitis A was laid in the 1970s, when virus was replicated in cell culture. Adaptation to growth in cell culture resulted in attenuation and sufficient quantities of virus particles, allowing the development of both live attenuated and inactivated vaccines. Testing of candidate vaccines in volunteers began in the early 1980s. Recently, a formaldehyde-inactivated whole-virion hepatitis A vaccine, the first licensed vaccine against hepatitis A, was introduced in many countries worldwide, and a live attenuated vaccine became available in the People's Republic of China. Other possible avenues for vaccine development include the use of either conventional or recombinant DNA techniques to obtain subunit vaccines, empty capsids, live viral or bacterial vectors, genetic immunization, synthetic peptides, and anti-idiotypes.

To investigate the long-term immunogenicity of an inactivated hepatitis A vaccine in children, 100 healthy children, aged between 1 and 7 years old and all lacking the antibody to hepatitis A (HA) virus, were enrolled in this trial. They received 3 doses of strain HM 175 HA vaccine with 360 enzyme-linked immunosorbent assay (ELISA) units at 0, 1 and 6 months, respectively. Blood sampling for antibody and aminotransferases was performed 7 days before, then 1, 6, 7, 12, and 24 months after the first dose. The titers of antibody to HA virus were tested by radioimmunoassay and ELISA methods. All subjects became ELISA seropositive at Month 6 after two doses of vaccine. Except for one boy, 99 remained seropositive at Month 24, with a geometric mean titer of 1,148 mIU/ml. Antibody titers for females were significantly higher than those for males throughout the follow-up period. It was concluded that the inactivated HA vaccine used in the present trial was immunogenic and safe in children below seven years old. The vaccine-induced antibody persisted for at least two years in 99% of the vaccinees.

Journal of Medical VirologyVolume 44, Issue 4 p. 442-442 Article Thermostability of an inactivated hepatitis A vaccine stored at 37°C for one week Prof. Dr. G. Wiedermann, Corresponding Author Prof. Dr. G. Wiedermann Institute for Specific Prophylaxis and Tropical Medicine, University of Vienna, AustriaInstitute for Specific Prophylaxis and Tropical Medicine, University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria===Search for more papers by this authorF. Ambrosch, F. Ambrosch Institute for Specific Prophylaxis and Tropical Medicine, University of Vienna, AustriaSearch for more papers by this authorF. E. André, F. E. André SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorA. Delem, A. Delem SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorE. D'hondt, E. D'hondt SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorA. Safary, A. Safary SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this author Prof. Dr. G. Wiedermann, Corresponding Author Prof. Dr. G. Wiedermann Institute for Specific Prophylaxis and Tropical Medicine, University of Vienna, AustriaInstitute for Specific Prophylaxis and Tropical Medicine, University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria===Search for more papers by this authorF. Ambrosch, F. Ambrosch Institute for Specific Prophylaxis and Tropical Medicine, University of Vienna, AustriaSearch for more papers by this authorF. E. André, F. E. André SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorA. Delem, A. Delem SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorE. D'hondt, E. D'hondt SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this authorA. Safary, A. Safary SmithKline Beecham Biologicals, Rixensart, BelgiumSearch for more papers by this author First published: December 1994 https://doi.org/10.1002/jmv.1890440423Citations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume44, Issue4December 1994Pages 442-442 RelatedInformation

A literature search was carried out to investigate the factors that influence the protective efficacy (PE) of hepatitis B vaccines when given to neonates of hepatitis B surface antigen and e antigen positive mothers. Hepatitis B vaccines with either high or low antigen doses are very effective in preventing chronic hepatitis B infection in neonates at risk, but there is evidence that with lower dosages simultaneous use of hepatitis B immune globulin (HBIG) administration is more important than with higher dosages to elicit good protection (PE > or = 90%). There is also a tendency for lower dosages to confer high PE less consistently, with noticeably greater numbers of chronic surface antigen carriers in neonates who received a complete vaccination course. Furthermore vaccination courses with higher vaccine dosages give high PEs, without concomitant HBIG administration at birth, provided that the first vaccine dose is given at birth and that the second dose follows within 2 months.

The association between elevated resting heart rate (RHR) as a cardiovascular risk factor and lowering of systolic blood pressure (SBP) to currently recommended values remain unknown. Systolic Blood Pressure Intervention Trial (SPRINT) data obtained from the NHLBI were used to describe the relationship between RHR and SBP reduction to <120 mmHg compared to SBP reduction to <140 mmHg. The composite clinical endpoint (CE) was defined as myocardial infarction, acute coronary syndrome, decompensation of heart failure, stroke, or cardiovascular death. Increased RHR was associated with a higher CE risk compared with low RHR in both treatment arms. A more potent increase of risk for CE was observed in subjects who were allocated to the SBP < 120 mmHg treatment goal. A similar effect of intensive and standard blood pressure (BP) reduction (p for interaction, 0.826) was observed in subjects with RHR in the 5th quintile (hazard ratio, 0.78, with 95% confidence interval (CI), 0.55–1.11) and in other quintiles of baseline RHR (hazard ratio, 0.75, with 95% CI, 0.62–0.90). Lower in-trial than baseline RHR was associated with reduced CE risk (hazard ratio, 0.80, with 95% CI, 0.66–0.98). We concluded that elevated RHR remains an essential risk factor independent of SBP reduction.

The immunogenicity and reactogenicity of an inactivated hepatitis A (HA) vaccine in children were investigated. One hundred three healthy children who lacked antibody to HA virus (anti-HA virus), aged between 3 months and 6 years 8 months, were enrolled in this study. They received three doses of 360 enzyme-linked immunosorbent assay units of HA vaccine in a 0-, 1- and 6-month schedule. Blood tests for aminotransferase and anti-HA virus were performed 7 days before and 1, 6 and 7 months after the first dose. Anti-HA virus was tested by radioimmunoassay and also by enzyme immunoassay for titer determination. The seroconversion rates measured by enzyme immunoassay were 95.1% (98 of 103) at Month 1 and 100% at Months 6 and 7. Nine percent (28 of 309) of the injections were followed by local symptoms, usually mild soreness and swelling at the site of injection, and 12% (37 of 309) by minor general symptoms. We conclude that HA vaccine is highly immunogenic and safe in children. It may replace immunoglobulin as an effective method to prevent HA virus infection in children. We also suggest that the HA vaccine be administered to children in endemic areas.