Doses Of Toxoid Research Articles

The Relationship of Immediate Wheal Reactions to the Repeated Administration of Diphtheria and Tetanus Toxoid

Summary Immunization with single vs. repeated doses of diphtheria toxoid was carried out in human subjects to determine the effects of the mode and schedule of administering this antigen upon antitoxin titers and upon immediate wheal responses. A similar study was carried out using repeated doses of tetanus toxoid. Schick positive persons who remained Schick positive did not develop wheal reactions to toxoid. Schick negative persons who were immunized orally did not show appreciable increases in antitoxin titer or in immediate wheal reactions. All Schick negative persons who received repeated parenteral doses of toxoid showed considerable increases in antitoxin titer and immediate wheal reactions until after the time that toxoid was discontinued. The same amount of toxoid given in one dose usually caused a marked increase in antitoxin titer up to about 3 weeks, and this was followed by a rapid decrease in titer. Wheal reactions were not present as frequently or in as marked degree in persons who received one dose of toxoid as in persons who were repeatedly immunized. Delayed reactions occurred many times in most Schick negative persons who received repeated doses of parenteral toxoid, but did not occur in persons who received only one dose of toxoid. Delayed reactions following a dose of toxoid generally occurred prior to the onset of immediate wheal reactions. Evidence is presented for the concept that immediate wheal reactions, as inflammatory responses, are coincidentally within the framework of the immune response. The degree of coincidence may be influenced by modes and schedules of immunization. These factors may be important in complex formation, and complexes may in turn provide the potential for wheal reactions.

Differences in Primary and Secondary Immunizability of Inbred Mice Strains

Summary Immunizability is defined in terms of amount of a given antigen that is necessary to confer a defined degree of immunity. Pure inbred mice strains were found to differ up to 10-fold in respect to primary immunizability, referring to immunity after one dose of tetanus toxoid. The same strains were tested with two doses of toxoid separated by various time intervals. Whatever the time interval, the strains differed in respect to the amount of the first dose necessary to confer immunity, and the order of immunizability found after two doses correlated with the primary immunizability. Although the regression of response on the first dose increased with time interval and was independent of strains, the regression of response on the secondary dose was independent of time—the flatter, the better immunizable the strain. Mean responses for the same set of doses showed a regular linear increase over three weeks. The results are interpreted in the light of current hypotheses on antibody production. Differences in immunizability are explained as differences in the ease and speed with which cells are first matured into specific antibody production cells whereas the rate of multiplication of these cells bears little or no relation to immunizability.

Production of Tetanus Antitoxin by Patients with Hepatic Cirrhosis

THE noteworthy effectiveness of active immunization against tetanus by means of tetanus toxoid has not obviated the use of equine antitoxin, since there is still a large segment of the population that has not been actively immunized. In addition, certain conditions in the presumably actively immunized person, such as uncertainty about immunization history, severe injuries about the head or neck, delay of twenty-four hours in treatment and the omission of a booster dose of toxoid for several years, are usually considered as indications for employing passive as well as active immunization when injury is sustained. Lastly, the rare occurrence of . . .

Eosinophil response to toxoids in actively and passively immunized mice.

SummaryI. Intraperitoneal injections of tetanus and diphtheria toxoid into actively immunized mice produce an accumulation of; eosinophil cells in the peritoneal fluid which reaches a peak at 4 days and lasts for at least 10 days. The degree of increase depends upon the dose of toxoid used. The local eosinophilia does not occur in non-immunized mice or in mice passively immunized with heterologous antibody. 2. The experiments suggest that the local eosinophilia is due neither to the antigen-antibody reaction nor to the accompanying inflammatory syndrome, but to an early stage of antibody formation during the secondary response.

Immunological Properties of a from of Non-Precipitating Diphtheria Antitoxin Which Does Not Sensitize Human Skin

Summary A type of human non-precipitating diphtheria antitoxin is described which is not able to cause immediate wheal reactions in appropriate recipients. Individuals who form this antitoxin following a booster dose of toxoid develop no immediate reactivity upon subsequent testing with intradermal toxoid. The sera of ten persons who formed only non-precipitating non-skin-sensitizing antitoxin were studied in detail and the following characteristics were observed. No fixation of complement occurred unless large amounts of antitoxin were used, and specific coprecipitation of antitoxin in two high titered sera resulted upon the addition of precipitating antitoxin and toxin. None of the sera tested were able to sensitize human skin, nor was there any evidence that this antitoxin remained at intradermal sites. When three sera containing the highest titers were separated electrophoretically, the antitoxin was found to migrate as a slow-moving gamma globulin (γ2). Three of seven sera were able to inhibit immediate reactions at sensitized sites when combined with equivalent amounts of toxoid. Four sera could not be evaluated for this property because they had an irritative effect when injected alone in the skin.

Tetanus immunization. XI. Study of the duration of primary immunity and the response to late stimulating doses of tetanus toxoid.

Although the protective value of active immunization with tetanus toxoid has been conclusively established, there remains in the minds of many practitioners and responsible public health personnel doubt concerning the effectiveness of stimulating injections and the duration of primary immunity. There is especially confusion relating to the length of time a person may go following primary immunity and still develop a protective response to a stimulating dose of toxoid. The following statements are generally accepted. A blood serum level of 0.1 ATU/ml. is protective against the development of clinical tetanus. A stated ATU level resulting from active immunization is far more effective protection than a corresponding level from passive immunization from the administration of antitoxin.1 Two or more doses (according to the manufacturers' specifications) of precipitated toxoid given at an interval of one to two months with a stimulating dose one year following the last dose of

Combined tetanus-diphtheria immunization of adults: use of small doses of diphtheria toxoid.

Combined Tetanus-Diphtheria Immunization of Adults: Use of Small Doses of Diphtheria Toxoid Affiliation Geoffrey Edsall, James S. Altman, and Andrew J. Gaspar CopyRight https://doi.org/10.2105/AJPH.44.12.1537 Published Online: August 29, 2011

Protective action of tetanus toxoid unrelated to active immunization in mice.

Summary1. Mice injected with a single dose (0.4 ml) of fluid tetanus toxoid 24 hours prior to, or simultaneously with a small dose (1 LD50 to 1 MLD) of tetanus toxin exhibited a degree of protection against the action of the toxin. The protective effect varied directly with the dose of toxoid. Toxoid given 3 or 5 days before the toxin afforded little or no protection. 2. Small daily doses of toxoid (0.1 ml) given over a 4-day period commencing 3 days prior, one day prior, or on the day of toxin administration were as efficacious in inhibiting the action of toxin as an equivalent single large dose of toxoid (0.4 ml) administered coincident with the injection of toxin. 3. When toxoid and toxin were mixed in vitro prior to injection into mice, the protective effect of the toxoid appeared to be enhanced.

Inherent Immunizability to Tetanus Toxoid, Based on Studies in Pure Inbred Mice

Summary Ten inbred mouse strains from Roscoe B. Jackson Memorial Laboratories were tested for immunity to tetanus toxin after treatment with graded doses of alum-precipitated tetanus toxoid. Some strains required about 0.005 ml toxoid to obtain a given immunity in 14 days, while other strains required a dose of toxoid 10 to 30-fold higher. The former are characterized as having high immunizability, the latter group as having low immunizability. All ten strains required the same median lethal dose of tetanus toxin when not immunized. It is concluded that susceptibility to toxin is distinct from immunizability.

Anaphylactic shock in the pertussis vaccinated mouse. II. Diphtheria and tetanus toxoids as antigens.

Summary1. Mice immunized by an intraperitoneal injection of a mixture of H. pertussis and diphtheria toxoid become markedly anaphylactogenic to a challenging dose of toxoid. 2. Under the conditions of the experiments described pertussis vaccine has no enhancing effect on the anaphylactogenicity of tetanus toxoids.

The Effect of Environmental Temperature on the Immune Response of Mice to Tetanus Toxoid

Summary Mice were immunized with single doses of fluid tetanus toxoid, from 5 to 20 flocculation units, and divided in groups which were maintained for 14 days at respectively 6 C, 25 C and 35 C. Subsequently, the animals were all transferred to room temperature and challenged with 20 lethal doses of tetanus toxin. Highest immunity was shown in the mice submitted to the warmer atmospheres during immunization, the difference being most distinct with a low dose of toxoid. Variation in response to toxoid occurred among animals of different litters, and necessitated equal distribution of litter mates over the treatments. The term immunizability is proposed to describe the inherent attributes of the host which determine the intensity of the immune response. Immunizability is distinct from factors of resistance which determine intensity of reaction to infection in non-immune animals.

IMMUNOCHEMICAL STUDIES OF ANTITOXIN PRODUCED IN NORMAL AND ALLERGIC INDIVIDUALS HYPERIMMUNIZED WITH DIPHTHERIA TOXOID

In Vol. 95, No. 4, April 1, 1952, the following sentence should be inserted in the paper by Drs. Kuhns and Pappenheimer on page 365, in the fifth line from the bottom:— The high antitoxin titer found at this time is explained by the fact that the boy had already received an earlier "booster" dose of toxoid a few months previously.

Qualitative differences among toxins and toxoids.

1. Considerable differences in antigenic efficiency are encountered among batches of (1) diphtheria toxoid, and (2) Cl. welchii (perfringens) toxins prepared under standardized conditions. These differences were revealed in the results of hyperimmunization of horses.2. Such differences in antigenic efficiency in batches of diphtheria toxoid were also detected by means of injections into guinea-pigs. Two injections, each of 2 Lf doses, were given at an interval of 28 days, and the response measured by means of antitoxin titrations on bleedings taken 10 days later.3. A general correlation was found between antigenic efficiency as measured by these two methods.4. A method is described for comparing the affinity for antitoxin, of batches of diphtheria toxoid, by determining the test dose of mixtures containing 9 Lf doses of toxoid and 1 Lr dose of a fixed toxin. The greater the avidity of the antitoxin, the more toxoid entered into combination with it.5. A correlation was found to exist between affinity for antitoxin and antigenic efficiency of toxoid, as measured both by the response of horses to hyperimmunization and the response of guinea-pigs to two spaced injections.6. It is tentatively suggested that crude toxoids may contain molecules possessing varying degrees of affinity for antitoxin, due to slight steric structural differences.

Antigenicity of Gas Gangrene Toxoids in Guinea Pigs, Mice, and Human Beings

Summary Cl. welchii and Cl. novyi toxoids have been assayed for antigenicity in mice, guinea pigs and human beings. It is felt that preliminary assay of these toxoids in guinea pigs shows a better correlation with the results in human beings than does the mouse assay. The antigenic response of guinea pigs to a single dose of alum-precipitated toxoid is a fair indication of the human response to two doses of the same toxoid. With divalent alum-precipitated toxoid containing 15 Lb of Cl. welchii toxoid and 60 L+ doses of Cl. novyi toxoid, detectable Cl. welchii antitoxin appeared in about 50 per cent and Cl. novyi antitoxin in about 75 per cent of the individuals given a primary course of two injections one month apart. Evidence is presented in the following paper (11) that a single booster dose given 5 to 6 months later will raise the proportion of individuals with detectable circulating antitoxins to at least 90 per cent. The antibody response to the booster dose of toxoid occurs between the seventh and ninth day after injection and reaches a peak by the fourteenth day. Local and systemic reactions to these toxoids have been for the most part mild, and typical of reactions observed routinely with alum-precipitated tetanal and diphtherial toxoids. Further work on methods for production of gas gangrene toxoids should greatly decrease the frequency and severity of such reactions.

Studies on Botulinum Toxoids, Types A and B

Summary and Conclusions Fluid and alum-precipitated botulinum toxoids were used to immunize man against botulinum toxin. There were no cases of botulism among individuals immunized with these preparations. A few individuals who were immunized received botulinum antitoxin immediately after a known gross exposure. An antitoxic level of 0.02 unit per ml of serum was selected as a presumptive protective level and was the objective in the immunological program of persons exposed. A schedule of 4 doses of fluid toxoid at 2 week intervals elicited antitoxic titers of the same magnitude as those titers attained by individuals on a schedule of 3 doses at 3 to 4 week intervals. On these schedules protective antitoxic titers were reached slowly, and not until after the last dose of toxoid was administered did more than half of the persons tested have a protective level of antitoxin. Attempts to increase the speed of the response by administering 4 doses of toxoid at weekly intervals or by administering a larger initial dose were unsuccessful. Within 5 months after starting immunization on a schedule of 4 biweekly injections of fluid toxoid over 90 per cent of the individuals had protective levels, and about 30 per cent had titers exceeding 0.1 of a unit per ml. This schedule was accepted for routine immunization, and because there appeared to be a gradual decline of the antitoxic titer after it reached a maximum at 5 months, booster injections were given every 6 months. These booster injections caused a rapid increase in the level of antitoxin present in the serum. Using alum-precipitated type A toxoid it was found that 3 injections at 3 to 4 week intervals was the most effective of the immunization schedules which were tested. The most important factor seemed to be the longer interval between the first and third injections. The importance of the time of injections was illustrated also in the experiments with a combined type A and type B alum-precipitated toxoid. A schedule consisting of 2 doses 8 weeks apart was more effective than one that called for 2 doses 3 to 4 weeks apart. Over three-fourths of the sera tested 2½ months after starting immunization, which had type B antitoxic titers classified as greater than 0.02 unit per ml, consisted of sera with levels exceeding 0.1 of a unit per ml. All of the data indicate that the best results were obtained by allowing a period of about 2 months to elapse between the first injection of toxoid and one of the subsequent injections. A small number of persons did not attain a measurable level of antitoxin in the serum. A study of the local and constitutional reactions caused by the combined alum-precipitated toxoid showed that moderate or marked reactions were few in number. Acknowledgement is made to Dr. Gail M. Dack, of the University of Chicago and Dr. N. Paul Hudson, of the Ohio State University for their continued interest and valuable advice throughout the course of the work. Acknowledgement is due Joanne R. Smith, Lt. (jg)H(S) and Pearl D. Fisher, Ens. H(S) USNR for their technical assistance.

Immunization of Humans and Animals with Gas Gangrene Toxoids

Summary Alum precipitated Cl. perfringens and Cl. oedematiens toxoids have been prepared from potent toxic filtrates. These toxoids have been demonstrated to be effective in producing a measurable and protective titer of antibodies in mice, guinea pigs, rabbits, goats, dogs and humans. In the animals, good protection against multiple doses of toxin and culture has been obtained. Protection of animals against heterologous as well as homologous strains of culture was demonstrated. Titers have been regularly achieved in humans which in smaller animals have shown good protection against toxin and culture challenge. In humans, very little rise of antitoxin titer was observed after one dose of Perfringens toxoid Lb=15. After two doses 50 to 75 per cent of individuals showed fairly good titers. When a third dose was given 3 to 9 months after the second dose excellent titers were obtained in practically all individuals and these titers were maintained for at least seven months. Good protective titers against Oedematiens were obtained with two doses of toxoid of as low a potency as 40 test doses (Lb=0.8). Very good response was obtained to a third dose of toxoid at 16 weeks after the second dose. Divalent toxoids (Perfringens-Oedematiens) have been prepared by mixing adequate amounts of the monovalent alum toxoids. These divalent toxoids have shown very adequate protective response (antibody titers and protection against toxin and culture) in mice, guinea pigs, rabbits and goats. Trials in humans have shown adequate response to three (3) doses of toxoid. The toxoids made for human use were prepared on a commercial scale and passed all safety tests as outlined by the National Institute of Health. The alum toxoids tested in humans did not produce local or systemic reactions in a great majority of the volunteers tested. Where reactions were obtained they were in a majority of the cases not as severe as those produced by alum tetanus or diphtheria toxoids or typhoid vaccine. Tests of the antigenicity of various toxoid preparations in mice and guinea pigs are given for comparison with the response subsequently obtained in humans. Data on the immunization of dogs and goats are also given.

Immunity to tetanus induced by a third dose of toxoid four years after basic immunization: Peshkin, M. M.: Am. J. Dis. Child. 69: 83, 1945

Immunity to tetanus induced by a third dose of toxoid four years after basic immunization: Peshkin, M. M.: Am. J. Dis. Child. 69: 83, 1945

Tetanus occurring in immunized individual: Case report

1. 1. A case of probable tetanus occurring in an American soldier previously immunized with three doses of fluid tetanus toxoid is reported. 2. 2. Tetanus under favorable conditions for bacterial growth, i.e., shock, extensive tissue destruction, hemorrhage, etc., may develop before any rise in the circulating antitoxin level from the stimulating dose of toxoid is obtained. 3. 3. It is suggested that in. all cases of shock, severe blood loss, extensive tissue damage, etc., tetanus antitoxin be administered to supplement active immunization.

PREPARATION AND IMMUNIZING PROPERTIES OF PROTAMINE DIPHTHERIA TOXOID

Alum-precipitated diphtheria toxoid is antigenically superior to "fluid" toxoid, since it elicits a higher titer of antitoxin when equal quantities (Lf) are injected. Fewer injections are consequently needed to produce a satisfactory immunity against diphtheria. However, both in adults and in adolescents its use frequently results in disagreeable reactions, largely local but occasionally systemic. There has been, therefore, a tendency to return to the use of "fluid" toxoid, even though it involves the extra burden of additional injections. Even this preparation produces in some adults reactions which are so annoying that the immunization may not be carried to completion. This eventuality may be avoided by resorting to very small doses of toxoid, but the objection to this method is the length of time it takes to administer the total volume required. The reactions are ascribed partly to bacterial body protein which goes into solution in the course of the autolysis

Immunity to tetanus induced by a third dose of toxoid two years after basic immunization: Based on a study of thirty-one allergic children: Peshkin, M. M.: Am. J. Dis. Child. 65: 873, 1943

Immunity to tetanus induced by a third dose of toxoid two years after basic immunization: Based on a study of thirty-one allergic children: Peshkin, M. M.: Am. J. Dis. Child. 65: 873, 1943