Persistence of antibody after administration of monovalent and combined live attenuated measles, mumps, and rubella virus vaccines.

Hemagglutination-inhibiting antibodies were retained in comparable levels eight years after vaccination with Enders' original Edmonston and more attenuated Moraten (Attenuvax) and Schwarz line measles vaccines. Neutralizing antibody persisted without substantial decline in titer for at least 9.5 years after administration of Jeryl Lynn mumps virus vaccine (Mumpsvax). Antibodies were retained without important decline in children and adults for at least 7.5 and 7 years, respectively, after administration of HPV-77 duck-modified rubella vaccine (Meruvax). The patterns of antibody persistence 7.5 years after administration of combined measles-mumps-rubella (M-M-R) and mumps-rubella (Biavax) vaccines, 6 years after administration of measles-rubella vaccine (M-R-VAX), and 4 years after administration of measles-mumps vaccine (M-M-VAX) were the same as for the monovalent vaccines, indicating no alteration in the retention of immunity. Subclinical reinfection evidenced by increase in homologous antibody titer was observed to follow vaccination the same as occurs after natural infection.

Long-term follow-up for immunity after monovalent or combined live measles, mumps, and rubella virus vaccines.

Antibody in human subjects persisted without substantial decline for 8 years after mumps vaccine (Jeryl Lynn), for 6 years after measles (Attenuvax), for 5 1/2 years after rubella vaccine (HPV-77 duck), for 5 years after measles-mumps-rubella and mumps-rubella combined vaccines, for 4 years after measles and rubella, and for 2 years after measles-mumps vaccines, the longest periods tested. Protective immunity against mumps illness persisted through the eighth year. The patterns for antibody following vaccination parallel those for natural infection and indicate that immunity will be lasting. Subclinical reinfection evidenced by antibody increase was commonly seen in persons who had been vaccinated, much as follows the natural infection.

Practical considerations in the production, purification, and formulation of monoclonal antibodies for immunoscintigraphy and immunotherapy.

Issues associated with the large-scale production of monoclonal antibodies for pharmaceutical applications are examined. The development of a commercial monoclonal antibody production process involves much more than just scaling-up the laboratory process and making it cost-effective. It involves establishing the hybridoma cell bank with cells that are free of adventitious agents such as viruses and mycoplasma, that have stability in continuous culture for antibody-production rate and cell viability, and that do not have unusual or expensive media requirements. The style and mode of operation of the bioreactor used to produce the antibody must be explored. The antibody-based product must be processed to high levels of purity, and specific contaminants such as DNA and endotoxin must be reduced to extremely low levels. Appropriate labeling or drug conjugation chemistries must also be developed. The product must be formulated so that it has performance characteristics that are stable over a reasonable period of time. Adequate test procedures must be developed to assure product purity, activity, stability, and safety on a lot-to-lot-basis. Compliance with federal regulations, guidelines, and procedures must be guaranteed. In the coming decade, it is likely that the two arms of biotechnology, hybridoma technology and recombinant DNA technology, will be used together to generate unique protein molecules. These new reagents will face the same practical considerations summarized in this review.

The preparation and safety of hepatitis B vaccine.

Preparation of hepatitis B vaccine in our laboratories consists of a series of steps that include initial concentration of surface antigen by ammonium sulphate precipitation, followed by isopycnic banding and rate zonal centrifugation in a K-II centrifuge. The partially purified antigen concentrate is digested with pepsin at pH 2 and the antigen is unfolded in 8 M urea solution followed by renaturation. After gel filtration, the antigen is treated with formalin in I :4000 dilution, adsorbed on to alum, and preserved with thimerosal. The final product contains essentially pure hepatitis B surface antigen. The process relies both on physical elimination of infectious virus particles and treatment with highly viral-destructive reagents in the pepsin (pH 2), urea and formalin steps. The process is known to be highly destructive of all known viruses tested and to include procedures that are known to be highly destructive of representatives of all known groups of animal viral agents. The three-step process in inactivation provides a fail-safe system for establishing safety of the product. Tests in more than 20000 persons, who are under surveillance, have shown no untoward effect and have confirmed the safety of the product.

Hepatitis B vaccine: a review of the clinical data to date.

The CDC estimates that about 200,000 Americans become infected with HBV each year. About 200 die of fulminant hepatitis. Most importantly, 12,000 to 20,000 persons become chronically infected, placing themselves at increased risk of developing chronic sequelae such as cirrhosis and primary hepatocellular carcinoma and also putting their families and close personal contacts at risk of hepatitis B infection. An effective vaccine to protect against hepatitis B is currently available. The vaccine is produced according to a rigorous process known to kill HBV, the agent causing AIDS, and all other viruses known to be present in human plasma. Well-controlled clinical studies have shown the vaccine to be well tolerated, immunogenic, and highly effective in preventing hepatitis B. The benefits of vaccination are clear.

Stress reactions in the job setting: case examples.

These four case illustrations may seem disparate, perhaps unrelated or disconnected. Yet, each tells its own story; each makes a separate series of points that fits the overall theme of this issue. Each heavily emphasizes the importance of psychodynamics in understanding cases of work stress. Each says to the practitioner, "Take the time to assess and understand an individual who comes to you reacting to his or her work." (I apologize to those readers who, once again, would criticize me for not including a case of a woman in this and the earlier chapter in this monograph series. In the last volume I leaned heavily on the research of Dan Levinson, which did not include women; in this, the points I wanted to make derived from experiences that happened to be with male patients.)

The troubled employee. Ages, stages, and vulnerability to stressors.

In the form of three detailed case studies, the author explains the timing and nature of emotional crises in employees. Context, vulnerability and specific stressors are discussed as components of work stress.

Development of vaccines against hepatitis A and hepatitis B.

Hepatitis A and hepatitis B are viral infections of the liver. Hepatitis A is spread by the fecal-oral route--i.e., by ingestion of virus shed in the stool of acutely infected individuals. The virus is transmitted from person to person or (in outbreaks) via contaminated food or water. Population groups at increased risk of acquiring hepatitis A include children and staff in day care centers. Hepatitis B is spread by blood and other body fluids from acutely infected individuals or chronically infected carriers. Infection occurs when virus contained in these fluids enters the body through mucosal surfaces or breaks in the skin. A vaccine against hepatitis B has been developed. It consists of noninfectious hepatitis B surface antigen purified from the plasma of chronic carriers. The three sequential inactivation treatments used in manufacture of the vaccine kill hepatitis B virus and other infectious agents that may be present in human plasma, including the human T cell-lymphotropic virus that causes the acquired immunodeficiency syndrome. The vaccine is well tolerated, highly immunogenic, and highly effective in preventing hepatitis B. Both live attenuated and killed vaccines against hepatitis A are also being investigated. A live attenuated vaccine is preferred and seems feasible on the basis of initial studies in animals and volunteers.

Prevalence of hepatitis B serologic markers in community hospital personnel.

The seroprevalence of hepatitis B markers among predominantly high-risk staff members and personnel of 31 community hospitals located throughout the United States was 8.4 per cent (greater than or equal to 5 per cent in 25 hospitals and greater than or equal to 10 per cent in 13 hospitals). Only two hospitals had seroprevalence rates less than or equal to 3 per cent. The institutional seroprevalence ranged from 0 per cent to 16.7 per cent, with a median of 8.2 per cent. Although there are limitations to this survey, the results suggest that the well established increased risk of contracting HBV infection among certain groups of health-care workers in urban teaching medical centers may also hold true for personnel in similar occupational and professional categories in community hospitals.

Factors regulating the secretion of lysophosphatidylcholine by rat hepatocytes compared with the synthesis and secretion of phosphatidylcholine and triacylglycerol. Effects of albumin, cycloheximide, verapamil, EGTA and chlorpromazine.

1. The synthesis and secretion of glycerolipid by monolayer cultures of rat hepatocytes was measured by determining the incorporations of [3H]glycerol, [3H]oleate and [14C]choline and by the absolute concentration of triacylglycerol. 2. The presence of albumin in the medium stimulated the accumulation of lysophosphatidylcholine in the medium by 11-13-fold. 3. Cycloheximide did not significantly alter the accumulation of lysophosphatidylcholine. 4. This process was particularly sensitive to inhibition by chlorpromazine and verapamil, compared with the secretion of triacylglycerol and phosphatidylcholine. By contrast, it was relatively less sensitive to EGTA. 5. It is suggested that intracellular Ca2+ may be important in the production of lysophosphatidylcholine, which then accumulates in the medium by binding to albumin. In vivo this lysophosphatidycholine may be a means of delivering choline and polyunsaturated fatty acids to other organs.

Quality and safety of human hepatitis B vaccine.

Preparation of hepatitis B vaccine in our laboratories consists of a series of steps that include initial concentration of surface antigen by ammonium sulfate precipitation, followed by isopycnic banding and rate zonal centrifugation in a K-II centrifuge. The partially purified antigen concentrate is digested with pepsin at pH2 and the antigen is unfolded in 8M urea solution followed by renaturation. After gel filtration, the antigen is treated with formalin in 1:4000 dilution, adsorbed onto alum, and preserved with thimerosal. The final product contains essentially pure hepatitis B surface antigen. The process relies both on physical elimination of infectious virus particles and treatment with highly viral-destructive reagents in the pepsin, urea and formalin steps. The process is known to be highly destructive of all known viruses tested and to include procedures that are known to be highly destructive of representatives of all known groups of animal viral agents. The three-step process in inactivation provides a fail-safe system for establishing safety of the product. Tests in more than 20'000 persons, who are under surveillance, have shown no untoward effect and have confirmed the safety of the product.

Progress toward a live attenuated human hepatitis A virus vaccine.

Human hepatitis A virus (HAV) was first grown in cell cultures four and one-half years ago, enabling significant progress toward the development of HAV vaccines. Vaccine development in a number of laboratories has proceeded on three fronts: 1) live, attenuated vaccine of cell culture origin; 2) inactivated vaccine of cell culture origin; and 3) genetic recombinant vaccines. Our studies to date have focused most heavily on the development of a live, attenuated HAV vaccine, although we have also made a prototype killed HAV vaccine form infected marmoset liver which induced anti-HAV and solid immunity to infection in marmosets. HAV was attenuated in virulence for both marmosets and chimpanzees by serial passaging in fetal rhesus monkey kidney cells and human diploid embryonic lung fibroblasts. A number of variants were produced which showed different levels of virulence/attenuation in these animal models. Some variants showed desirable live vaccine-like properties (little or no induction of enzyme elevations; little or no liver histologic change; retention of anti-HAV induction capacity). Vaccinated animals were solidly immune to challenge with virulent HAV. Experimental vaccines have been prepared from several attenuated HAV variants and preliminary studies in humans are planned.

Seroepidemiologic investigations of human hepatitis caused by A, B, and a possible third virus.

Seroepidemiologic studies were made of normal subjects in populations in the United States and Costa Rica and in family outbreaks of hepatitis in Costa Rica. Hepatitis A affected a majority of children of very young age in Costa Rica, while such experience in persons of high socioeconomic status in the United States did not occur before middle life. Persons of low socioeconomic status (paid plasma donors) and residents and attendants of institutions for the mentally retarded showed a far greater incidence of hepatitis A antibody than did their counterparts in the open community. Hepatitis A and B epidemics occurred in families in Costa Rica with rapid spread to other susceptible members of the group. The disease was clinically apparent in roughly half the cases, whether the responsible agent be hepatitis A or B. Five cases of nonhepatitis A or B (hypothetical hepatitis C) were found and all but one of them were subclinical.

Polyvalent pneumococcal polysaccharide vaccines.

A 14-valent pneumococcal vaccine has recently been licensed for general use after extensive testing in human subjects. Antibody production was satisfactory in 92% of individuals and a highly significant (76-92%) reduction was found in the rates for pneumococcal pneumonias caused by the capsular types present in the vaccine. Children over 2 years of age respond well to the vaccine, but younger children may not respond satisfactorily to some capsular types. In adults, the duration of the protective effect is at present unknown, but no substantial booster response was seen after a second dose at 1 year. Such a booster dose, in fact, induced a marked increase in the degree of local reaction at the injection site.

Clinical evaluation in healthy adults of a hepatitis B vaccine made by recombinant DNA.

A vaccine formulated from hepatitis B surface antigen (HBsAg) produced by a recombinant strain of the yeast Saccharomyces cerevisiae was administered to two groups of human volunteers composed of 37 healthy, low-risk adults. Each subject received a 10-micrograms dose of HBsAg at 0, 1, and 6 months. By one month, 27% to 40% of the vaccinees had antibody to HBsAg, and by three months 80% to 100% were antibody positive. Large boosts in titer followed the third dose at six months. The antibody formed is predominantly specific for the a determinant of HBsAg. There have been no serious reactions attributable to the vaccine. The most frequent complaint has been transient soreness at the injection site. As far as we know, this is the first reported use in man of a vaccine prepared by recombinant DNA technology.

Streptococcus pneumoniae polysaccharide vaccine: age and dose responses, safety, persistence of antibody, revaccination, and simultaneous administration of pneumococcal and influenza vaccines.

Contemporary 14-valent pneumococcal polysaccharide vaccine was first licensed in 1977 in the United States, where about four million doses of vaccine have been distributed to date. The vaccine induces excellent antibody responses in elderly persons as well as in young adults. The antigen content of the vaccine is 50 microgram of each serotype of polysaccharide per dose, and lower titers of antibody are induced when the dose is reduced to 25 or 12.5 microgram of antigen. Adverse reactions are usually mild and consist principally of local erythema and induration at the injection site, with mild fever in a small proportion of subjects. Antibody persists well for at least four years, and it is expected that immunity will last for at least 5 years after vaccination. Local and systemic reactions to the vaccine may be greater when a second dose of vaccine is administered within three years after the initial dose, and this reactivity appears to be due to a Arthus-like response that results from local formation of antigen-antibody complexes. Pneumococcal and influenza vaccines can be injected simultaneously into separate sites without impairment of antibody responses to either vaccine; this feature should facilitate administration of these two vaccines.