Universal mass vaccination against hepatitis A.

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--he 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.

Summary of safety and efficacy data on a yeast-derived hepatitis B vaccine.

Recombinant deoxyribonucleic acid technology has permitted the development of a vaccine from the hepatitis B surface antigen expressed in genetically manipulated yeast cells. Clinical trials with the vaccine were started in February 1984 and, to date, have involved more than 12,500 persons. The vaccine has been shown to be safe, well tolerated, and immunogenic in healthy persons of all ages and in special target groups likely to require vaccination. The vaccine's protective efficacy has been established in three groups at high risk for hepatitis B infection--homosexual men, institutionalized mentally handicapped patients, and neonates of mothers who are chronic carriers. Production of this vaccine on a large scale should make it less expensive than plasma-derived vaccines and thus broaden the indications for vaccination.

Protective efficacy of a recombinant deoxyribonucleic acid hepatitis B vaccine in institutionalized mentally handicapped clients.

Mentally handicapped clients in institutions are at high risk for hepatitis B virus (HBV) infection. In 1985, 770 mentally handicapped residents from four institutions in the Antwerp area were screened for HBV markers. The prevalence of hepatitis B surface antigen was 10.3 percent (range, 6.1 to 15.2 percent); 42.3 percent (range, 11.5 to 60.1 percent) had antibodies to hepatitis B surface antigen and the hepatitis B core antigen. In 1986, 275 seronegative mentally handicapped residents were vaccinated intramuscularly in the deltoid region with 20 micrograms (1.0 ml) of a recombinant deoxyribonucleic acid yeast-derived hepatitis B vaccine (Engerix-B, SmithKline Biologicals, Rixensart, Belgium) on a zero-, one-, six-month schedule. Serum samples were collected at Months 1, 2, 7, 12, and 24 and were tested for HBV markers by radioimmunoassay. The seroconversion rates for hepatitis B surface antigen antibodies were 39 percent at Month 1 (geometric mean concentration, 6.4 IU/liter), 82 percent at Month 2 (geometric mean concentration, 23.4 IU/liter), 97 percent at Month 7 (geometric mean concentration, 1,034 IU/liter), and 96 percent at Month 12 (geometric mean concentration, 269 IU/liter). Among the 214 residents evaluated at Month 12, 69 percent had hepatitis B surface antigen antibody levels greater than 100 IU/liter (geometric mean concentration, 603 IU/liter). No significant adverse reactions were observed. Within the first seven months of observation, HBV infection was detected in eight of 271 subjects (estimated annual incidence of 5 percent). During this period, none of the clients developed clinical hepatitis or showed biochemical evidence of liver damage. Between eight and 24 months, no additional HBV infections were detected. These data can be compared with an annual incidence of HBV infection of 8.7 percent in a historical cohort of mentally handicapped residents in one of the four institutions.

Evaluation of two tetravalent (ACYW135) meningococcal vaccines in infants and small children: a clinical study comparing immunogenicity of O-acetyl-negative and O-acetyl-positive group C polysaccharides.

Two different tetravalent polysaccharide vaccines against group A, C, Y, and W135 meningococci were given to 118 infants aged 6 to 23 months; the same vaccines were administered in a second dose 12 months later to those infants aged 6 to 11 months at first vaccination. Forty of the infants received vaccine containing the nonacetylated group C polysaccharide C(OAc-) and 78 the acetylated group C polysaccharide C(OAc+) together with group A, Y, and W135 polysaccharides. All polysaccharides, at a dose of 30 micrograms, induced antibody responses after administration of both vaccines in all age groups although the responses were better in the older infants. Acetylation of the sialic acid of the group C polysaccharide did not significantly influence the response. Rapid decreases in the antibody titers after the first vaccination stressed the need for one or more revaccinations. Vaccination elicited mild local and systemic reactions. Elevated temperatures were more common in the youngest infants but only four developed fever exceeding 38.5 degrees C (101.3 degrees F). We conclude that tetravalent (ACYW135) meningococcal vaccine is safe and immunologically effective in children younger than age 2 years. However, revaccinations may be required to maintain immunity.

Neonatal rotavirus vaccination with RIT 4237 bovine rotavirus vaccine: a preliminary report.

We vaccinated 244 newborn infants orally with RIT 4237 bovine rotavirus vaccine or placebo and followed them serologically and clinically for 16 months. Initially 39 of the 119 (33%) vaccine recipients compared with 1 of the 120 placebo recipients seroconverted by enzyme-linked immunosorbent assay-immunoglobulin M. After the first winter rotavirus season, at 7 months of age 55% of the vaccinated infants and 37% of the unvaccinated infants were rotavirus-seropositive by enzyme-linked immunosorbent assay-immunoglobulin G (P less than 0.01, chi square test). At 12 months of age, after a low rotavirus prevalence season, 34% of the vaccinated children and 23% of the unvaccinated children remained seropositive. There were 14 confirmed episodes of rotavirus gastroenteritis in the vaccine group and 10 episodes in the placebo group during the first 16 months. However, only 1 of the episodes in the vaccine group was severe, 4 were moderately severe and 9 were mild, whereas 7 episodes in the placebo group were severe and 3 were moderately severe (P less than 0.001 between groups, Fisher's exact test). There was no clear correlation between vaccine-induced clinical protection and initial serologic response (enzyme-linked immunosorbent assay-immunoglobulin M) to vaccination, but during follow-up severe rotavirus gastroenteritis was more likely to occur in children with no serum rotavirus immunoglobulin G antibody at the time of infection. We conclude at the present stage that neonatal rotavirus vaccination with RIT 4237 vaccine gives no protection against rotavirus infection but appears to modify the severity of gastroenteritis.

Safety and immunogenicity of hepatitis A vaccine in healthy children.

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.

Measles, mumps and rubella immunization at nine months in a developing country.

The antibody responses and reactogenicity of a measles, mumps and rubella vaccine in 9-month-old and 15-month-old black children in South Africa were compared. The antibody response to the measles component was marginally better in the older group, but no differences were observed in the response to the mumps and rubella components. Reactogenicity was similar in the two age groups. Therefore it is possible that a trivalent measles, mumps and rubella vaccine can safely and effectively replace routine measles immunization at 9 months of age in this population. Whether routine immunization policy should incorporate such a vaccine depends on the extent of acceptance of measles vaccination. In urban populations of developing countries with high rates of measles immunization, routine vaccination at 9 months might interrupt circulating wild type rubella and provide sufficient herd immunity to protect susceptible women of childbearing age. It also should decrease significantly the complications associated with wild type mumps infection. The replacement of measles vaccine by a trivalent vaccine may be very cost-effective.

How the research-based industry approaches vaccine development and establishes priorities.

Over the past two decades, progress in immunology, molecular biology and genomics as well as some technological breakthroughs in computer science has opened the way to the development of prophylactic vaccines against most acute infectious diseases. Therapeutic vaccines against chronic infections, allergic conditions, auto-immune diseases and cancer have also come into the realm of possibility. It is estimated that wordwide there are about 400 vaccine projects in R&D laboratories of academic institutions, research institutes and vaccine manufacturers. Most of these projects will not yield a licensed vaccine for routine or even targeted immunisation. This is mostly not because of scientific barriers but due to financial and politicoeconomic obstades that make their development feasible only by the handful of major research-based vaccine manufacturers that nowadays all form part of large global pharmaceutical corporations. Such enterprises have to be profitable to survive and priority setting, when it comes to R&D projects, has to take into account potential return on all investments, particularly as it currently costs between 200 and 500 million US dollars to bring a new vaccine from the concept stage to market. Factors that influence the decision to embark upon an R&D project on a new vaccine include the medical need for the vaccine, gauged by the global burden of the targeted disease, potential and probable market size - judged on volume (number of doses required) and value (total sales) -, probability of success and expertise of the company in the field (both R&D and marketing) as well as the likelihood of competitors taking a large part of the market. Moral imperatives such as the urgent need for vaccines against HIV/AIDS, malaria and an improved vaccine against tuberculosis to save the several millions of lives claimed each year by these diseases also play a role. However, for such investments to be sustainable other sources of financing than the commercial market will be required.

Strengths and weaknesses of current polio vaccines--a view from industry.

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.

Clinical experience with a recombinant DNA hepatitis B vaccine.

The clinical testing of EngerixR-B, the hepatitis B vaccine produced by SmithKline Biologicals using recombinant DNA technology, started in February 1984. Since extensive pre-clinical laboratory work had established that the polypeptide (HBsAg) expressed in genetically engineered yeast cells was after purification--physically, chemically and antigenically similar to the viral surface antigen particles found in the blood of chronic carriers, the aims of the clinical trials were to compare the safety, reactogenicity, immunogenicity and protective efficacy of yeast-derived (YDV) and plasma-derived (PDV) vaccines. By September 1987, 89 studies had been initiated involving a total of 10,545 subjects aged from birth to 82 years. This extensive experience has established that the risk of hypersensitivity to yeast-derived contaminants is negligible since no hypersensitivity reaction has been observed in any vaccinee, the incidence and severity of local reactions have not increased after repeated inoculations and no anti-yeast antibodies were produced by vaccination. Reactogenicity has been comparable to that of PDV's consisting essentially of transient mild irritation at the site of injection presumably caused by the aluminium hydroxide used as adjuvant. The anti-HBs responses to YDV and PDV's were quantitatively (seroconversion rates, peak antibody levels and persistence) as well as qualitatively (epitope specificity and affinity) similar. The expected protective effect of the immune response to the vaccine was confirmed in a challenge study in chimpanzees and in vaccinated human populations (male homosexuals, institutionalized mentally retarded patients, neonates of carrier women) with historically a high infection rate.

Vaccination greatly reduces disease, disability, death and inequity worldwide.

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.

Approaches to a vaccine against hepatitis A: development and manufacture of an inactivated vaccine.

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.

Development of combined vaccines: manufacturers' viewpoint.

Rapid and exciting research breakthroughs in the fields of immunology and molecular biology in recent years have greatly enhanced the potential for developing new vaccines or improving existing ones. The resulting rising number of diseases that can be prevented by vaccination, coupled with the growing trend of preferring cost-effective preventive medical interventions over expensive therapeutic modalities, has increased the complexity of administering to all those who need them, the many different vaccines that will soon be available. Hence attention in the field of vaccinology is now focusing on the development of combined vaccines that, in a few inoculations, can elicit protection against as many diseases as possible. Some of the recent achievements, future objectives and difficulties of vaccine manufacturers in the development of combined vaccines are surveyed.

New developments in vaccinology.

PIP: New vaccine developments will reflect achievements of the World Health Organization's (WHO) Expanded Programme on Immunization (EPI), as well as resistance from the public toward increasing numbers of vaccines. WHO's EPI program has concentrated on tuberculosis, diphtheria, tetanus, whooping cough, polio, and measles. 35 countries are attempting to control hepatitis B with universal vaccination. Now some countries are also recommending vaccination against Haemophilus influenza, mumps, and rubella. The complexity of multiple injections has prompted new research on acellular vaccines for pertussis, hepatitis A and B, varicella, and malaria. Combined vaccines and new adjuvants are also targets of intense research. Vaccines are a priority, because they are among the most cost-effective of medical interventions.^ieng

Development and clinical application of new polyvalent combined paediatric vaccines.

The availability of combined vaccines containing protective antigens against the majority of (ideally all) diseases for which universal immunization is recommended in infancy would simplify the implementation, increase the acceptance, reduce the global cost of immunization programmes and improve disease control, while offering the possibility of disease elimination or even pathogen eradication. The desirability of combined vaccines is further enhanced, and made more urgent, because of the increasing number of diseases that can be prevented by vaccination. The complicated logistics of administering different vaccines that each require several inoculations is a significant barrier to successful immunization of a population. Furthermore, interest in immunization is continuously gaining momentum since it is now generally recognised that vaccines are among the safest and most cost-effective medical interventions for infectious diseases that continue, in spite of the widespread use of efficacious antimicrobial drugs, to be an important cause of morbidity and mortality. This burden is likely to increase due to the development of antimicrobial resistance. Basic research on new vaccines or improvement of existing ones such as the use of new technologies may be carried out in academic or other non-industrial laboratories but development work, including the necessary extensive clinical testing, that lead to products that can be approved for routine use is usually co-ordinated and financed by commercial companies. The decision to develop any particular combined vaccine will therefore be influenced not only by its medical desirability and technical feasibility but also the potential financial returns that the required investments in time and resources may bring to the company. All major vaccine manufacturers are currently working, either alone or through strategic alliances, towards developing more polyvalent vaccines by adding antigens such as inactivated polio virus, conjugated Haemophilus influenzae type b polysaccharide and hepatitis B surface antigen to the diphtheria-tetanus-pertussis vaccine either in its 'classical' (whole-cell) or more purified (acellular) formulations. Experience is showing that the development of combined vaccines involves much more than the simple mixing of existing antigens. Possible incompatibilities or mutual interferences between the antigens themselves, or between excipients, preservatives, adjuvants, residual contaminants, stabilisers and suspending fluids make it mandatory that each formulation be thoroughly tested for quality, stability, efficacy and safety. Furthermore the ability to produce and control it consistently must be established before it can be licensed for commercial use. The progress being made in this field is reviewed.

The future of vaccines, immunisation concepts and practice.

Vaccines have prevented more deaths, disability and suffering than any other medical discovery or intervention. Recent breakthroughs in immunology and genomics offer the prospect of the development of many new prophylactic and therapeutic vaccines not only against infectious diseases but also for use in conditions such as allergy, autoimmunity and carcinogenesis where malfunction of the immune system undoubtedly plays a role. These hopeful perspectives are however dimmed by several counterproductive societal trends that include the spreading-although unjustified-belief that vaccines are not safe and may even be unnecessary, escalating costs of vaccine research, development, production and control that are exacerbated by political pressure on selling prices and expensive lawsuits by 'victims' of vaccination who claim excessive compensation. Negative media coverage of vaccine issues is adversely affecting acceptance of vaccination. In spite of these negative trends, vaccines should have a bright future, because it is increasingly being realised that prevention is not only better than cure but it is often also more cost-effective. A better understanding of the dynamics of microbial transmission in populations is leading to more rational immunisation practices on a global scale that could lead to eradication of several pathogens. Attention is being given to making vaccines more user-friendly through the development of combined vaccines and the introduction of less invasive inoculation techniques.

Overview of a 5-year clinical experience with a yeast-derived hepatitis B vaccine.

Since February 1984, 122 clinical trials have been conducted with a rDNA yeast-derived hepatitis B vaccine (YDV) and plasma-derived vaccines (PDV), involving more than 14,800 individuals. The vaccine has proved safe and well tolerated in all age groups as well as highly immunogenic in both healthy subjects and special target populations. Antibodies elicited by the YDV were qualitatively and quantitatively similar to those induced by PDV. The protective efficacy of the recombinant vaccine has been established in three groups at high risk for hepatitis B infection: the institutionalized mentally handicapped, homosexual males and neonates of carrier mothers. The recombinant vaccine may therefore be considered to be an alternative to PDV and will be invaluable in the control of hepatitis B.

Worldwide experience with the Oka-strain live varicella vaccine.

Sufficient safety and efficacy data have been obtained on a live varicella vaccine (Varilrix, Smith Kline-RIT) derived from the Oka-strain attenuated varicella-zoster virus to justify its recent licensure in several European countries for use in special indication groups. This review article summarizes the data obtained in Japan, Europe, and the United States. In addition, a survey of the published literature on clinical studies performed on as yet unlicensed Oka-strain varicella vaccines produced by the Biken Institute and Merck Sharp & Dohme is presented.