SEVERAL “MIXED” VACCINES NOT ADMITTED TO N. N. R.

Report of the Council on Pharmacy and Chemistry

The “mixed” vaccines which are discussed in the reports that follow were considered by the Council during the past year because inquiries had been received in regard to them.

In publishing these reports it is desirable that the attitude of the Council toward “mixed” vaccines again be stated. In view of the rapid development of bacterial therapy, the possibility for harm that attends the use of bacterial vaccines and the skepticism among experienced clinicians as to the value of vaccines representing a combination of organisms, the Council has felt that it should scrutinize the claims for such agents with exceptional care and that there should be admitted to New and Non­official Remedies only those vaccine mixtures for which there is acceptable evidence to indicate that the use of the particular mixtures is rational.

In considering the subject the Council has borne in mind the fact that in many institutions in which cases are studied and the results of therapeutic measures carefully observed and controlled, vaccines of any sort are practically never used—certainly here the stock mixed vaccine has no recognition. Experienced clinicians have generally come to the conclusion that mixed vaccines have no specific action and that any effect they may produce is due to a non-specific protein reaction.

As set forth in the reports, in no case was the evidence submitted by the proprietors sufficient to establish the claims made for the preparations. Hence none was accepted for New and Non­official Remedies.

The preparations that form the basis for the accompanying reports are only a few of the many that are being made and sold by some biological houses. Doubtless many of those not dealt with in this report are equally irrational and sold under claims equally—or probably even more—unwarranted than those with which the present report deals.

W. A. Puckner, Secretary.

Mixed Vaccines-Abbott

In response to inquiry the Council undertook a consideration of the following “mixed{”} vaccines sold by the Abbott Laboratories:

M. Catarrhalis-Combined-Bacterin, said to contain killed Micro­coccus catarrhalis, Bacillus Friedländer, Pneumo­cocci, Strepto­cocci, Staphylo­coccus aureus and Staphylo­coccus albus.

B. Coli-Combined-Bacterin, said to contain killed Strepto­coccus viridans, Strepto­coccus hemo­lyticus and Bacillus coli.

Pertussis-Combined-Bacterin, said to contain killed Bacillus pertussis, Pneumo­cocci, Strepto­cocci, Staphylo­coccus albus, Staphylo­coccus aureus and Micro­coccus catarrhalis.

Strepto­coccus-Rheumaticus-Combined-Bacterin, said to contain killed “Strepto­cocci (Rheumaticus, Viridans, etc.)” and Pneumo­cocci.

Strepto­coccus-Viridans-Combined-Bacterin, said to contain killed Strepto­coccus viridans, Strepto­coccus hemo­lyticus, Pneumo­coccus and Staphylo­coccus albus.

The Abbott Laboratories were asked to assist in the investigation of these products and to submit evidence to establish their eligibility for admission to New and Non­official Remedies. The manufacturer was informed that the Council accepts “mixed” vaccines or bacterins, provided the usefulness of these products is established by acceptable clinical evidence, and references to the literature bearing on the value of the preparations were requested.

The Abbott Laboratories submitted specimens of the products, the advertising matter therefor and a considerable list of references to current literature; all of which was transmitted to the Committee on Serums and Vaccines for consideration. In due time a referee of the committee submitted the following report:

THE COMMITTEE’S REPORT

The referee has studied the literature covered by the references submitted. In general the articles are favorable to the use of vaccines, though many of these papers do not consider “mixed” vaccines; indeed, a number of the articles do not discuss treatment at all, but are devoted entirely to the consideration of etiology of the disease. Many of the papers are by those who are obviously overenthusiastic on the subject of the use of biologic preparations. One paper—not included in the references submitted by the Abbott Laboratories—records an alarming reaction following a dose of mixed vaccine; no claim is made that improvement followed.

The following comments on the submitted references are offered:

M. Catarrhalis-Combined-Bacterin.—Only four of the nine references given deal with the therapeutic use of the vaccine. The reported results in general were favorable, but sometimes in the discussion evoked by certain of the papers, views the reverse of those expressed by the author were brought forward. The enthusiasm of one writer is shown in his statement that following the use of vaccine in cases of carbuncle complicating diabetes the sugar in the urine disappeared or was reduced. One observer, who reports excellent results in nasal pharyngeal catarrh, speaks of certain vaccines as “bulk goods,” while another considers “——’s No. 7” as the proper thing. It is evident that the reports are not based on careful, scientific data, or such unscientific definition of the product employed would not be used.

B. Coli-Combined-Bacterin.—In the references cited in support of this preparation the following general statements are noted: One enthusiastic writer says, “It must be recognized that we have no satisfactory explanation of the action of vaccines, and their use at present is empirical.” One author dwelt on the superiority of autogenous vaccines but admits that occasionally stock vaccines are indicated. One vaccine therapist in concluding an article states, “It is simply impossible to practice modern urology without our modern biologic products.” Yet it is a well-known fact that many successful and capable genito-urinary surgeons avoid the use of vaccines, mixed or simple.

Pertussis-Combined-Bacterin.—These reports are uniformly favorable, but are not controlled and their value is not to be compared with a recent report from the New York City Department of Health which indicates that the vaccine is practically valueless. It is noted, further, that one of the articles cited which dealt rather fully with the treatment of pertussis did not mention vaccines.

Strepto­coccus-Rheumaticus-Combined-Bacterin.—The references cited in support of the preparations by the manufacturer give no support whatever for the use of mixed stock vaccines. The first reference deals with the relation of Strepto­coccus viridans to arthritis deformans and endocarditis and reports the following cases:

Case 1.—Vaccine case—improvement after eight months.
Case 2.—Slight improvement following use of vaccine.
Case 3.—Slight improvement following use of vaccine.
Case 4.—Marked improvement.
Case 5.—Prompt improvement.
Case 6.—Vaccine not mentioned.
Case 7.—Vaccine followed by slight improvement.

In each of the cases other methods of treatment were used. The paper shows the etiologic relation of Strepto­coccus viridans rather than the value of vaccines. There is no indication that stock vaccines were used, though the paper is not clear on this point. The second paper deals with the application of vaccine therapy in the treatment of arthritis. This paper is by a man who is avowedly an enthusiast on vaccine therapy. The indications are that he generally used a mixed autogenous vaccine, but the reports of cases are not always clear. This writer apparently makes no serious attempt at the classification of the joint conditions he treats. The third reference is a purely experimental study and has no bearing on the use of vaccines in treatment. The fourth article was admitted by the manufacturer to be “negative as regards evidence.” The fifth reference specifically states that “the vaccine must be autogenous.” The sixth reference deals with the experimental production of appendicitis by the use of diplococci, and has not the most remote bearing on the use of vaccines in the treatment of rheumatism.

Strepto­coccus-Viridans-Combined-Bacterin.—The article which bears evidence of more care than the others admits that we are not in position to state the value of vaccines in pyorrhea but the author believes they may have value supplementary to local treatment.

It is not surprising that a large number of favorable reports can be accumulated when we appreciate how promptly men report what they consider to be their successes and how commonly they leave their failures unrecorded. Bearing in mind the fact that these stock mixed vaccines, though before the profession for many years, have not been used, or continued in use, in hospitals where work is rigidly controlled and that they are used practically not at all in the large government hospital service, a candid critic must hold that there is no substantial evidence in favor of the therapeutic use of a mixed vaccine, certainly not for stock “goods” and that probably there is but a limited field for the employment of autogenous vaccines.

The referee calls attention to a shift in the advertising matter on vaccines—the tendency to recommend vaccines to be used in conjunction with drugs. A heading in the Abbott booklet reads, “The Biologics Do Not Replace Drugs”; and the paragraph speaks of serums and bacterins as “new tools, supplemental to those we already have, but not replacing them.” ... “We need them both.”

The referee recommends that the several mixed vaccines discussed in this report be not accepted on the grounds that satisfactory evidence of their value is wanting.

Having been endorsed by the Committee on Serums and Vaccines the Council adopted the report and declared M. Catarrhalis-Combined-Bacterin, B. Coli-Combined-Bacterin, Pertussis-Combined-Bacterin, Strepto­coccus-Rheumaticus-Combined-Bacterin and Strepto­coccus-Viridans-Combined-Bacterin ineligible for admission to New and Non­official Remedies.

Catarrhal Vaccine Combined-Lilly and Influenza Mixed Vaccine-Lilly

Because of inquiry received, the Council requested Eli Lilly and Company to aid in determining the acceptability of the following products for New and Non­official Remedies: “Catarrhal Vaccine Combined,” said to contain killed cultures of the Bacillus of Friedländer, Micro­coccus catarrhalis, Staphylo­coccus aureus and albus, Pneumo­coccus and Strepto­coccus; “Influenza Mixed Vaccine,” said to contain killed cultures of Staphylo­coccus albus and aureus, Strepto­coccus, Pneumo­coccus, Micro­coccus catarrhalis and Bacillus influenzae.

Lilly and Company sent the circulars, etc., used in advertising these products. A circular for “Catarrhal Vaccine Combined” contained the following claim:

“Catarrhal Vaccine has been especially useful in many respiratory infections, including bronchitis, pharyngitis, rhinitis, chronic catarrh and in the mixed infections of pulmonary tuberculosis.”

A circular for “Influenza Mixed Vaccine” contained the following:

“The vaccine is useful in the treatment of influenza and ordinary colds, and in any infection in which the Bacillus influenzae is the causative agent.”

An advertising pamphlet contained the following:

“Catarrh, Acute and Chronic; Colds, Influenza.—The micro-organisms capable of producing catarrhal conditions of the nose and pharynx and most commonly isolated are B. Friedländer, M. catarrhalis, staphylo­coccus, pneumo­coccus (in infections beginning in the larynx), B. influenza and strepto­coccus. These organisms are found normally in the respiratory passages and acquire virulence only when resistance has been lowered through overwork, exposure to cold, etc.

“The results following the use of Catarrhal Vaccine Combined (in the non-epidemic forms) and influenza Mixed Vaccine (in the epidemic types) have been very satisfactory, due to the great vascularity of the tissues. Acute attacks are aborted altogether or shortened in duration and the danger of complications greatly minimized.”

No evidence was submitted which warrants the preceding claims nor is the Council aware of any reliable testimony to indicate that the administration of the mixture here discussed is warranted or desirable. On the recommendation of the Committee on Serums and Vaccines the Council voted that “Catarrhal Vaccine Combined-Lilly” and “Influenza Mixed Vaccine-Lilly” be not included in New and Non­official Remedies because satisfactory evidence of their value is wanting.

Influenza Serobacterin Mixed-Mulford

Because of inquiry received, the Council took up the consideration of “Influenza Serobacterin Mixed-Mulford,” and requested the Mulford Company to present evidence to establish the admissibility of the preparation to New and Non­official Remedies. The Mulford Company sent specimens of the serobacterin in question, an advertising circular and a letter by the director of its Biologic Laboratories.

According to the label on the package, the preparation is made from the following organisms: Bacillus influenzae, Staphylo­coccus aureus, Staphylo­coccus albus, Strepto­coccus, Pneumo­coccus and Micro­coccus catarrhalis (group). This mixture is recommended by the manufacturer:

“For the prophylaxis and Treatment of Common Colds, Mixed Infections of the Respiratory Mucous Membranes, Acute and Chronic Catarrhal Conditions of the Nose, Throat and Respiratory Passages.”

No evidence is submitted for this recommendation except that in “colds and bronchitis and the other common infections of the upper respiratory passages ... five or six bacteria are very commonly present—two or more of them are nearly always present ...” and the letter by the director of the Mulford Biologic Laboratories expressing the belief that in his own case the use of the mixed vaccine has aborted or prevented colds.

As regards the use of this complex biologic preparation:

First, the cause of common colds is, at the present time, quite unknown. One of the most striking things is that at the beginning of a cold the organisms to be cultivated from the nasal mucous membrane are very few in number and there is no uniformity in the type of organism found. If someone of the well-known organisms (Strepto­coccus, Staphylo­coccus, Pneumo­coccus, Micro­coccus Catarrhalis, Influenza Bacillus, etc.) were responsible, we should expect to find one of them preponderating and in overwhelming numbers. This is far from the case. After the duration of the cold for a day or two with the increased production of mucus and apparently with the infection of a mucous membrane whose powers of resistance have been greatly lowered, bacteria of all kinds are to be found in immense numbers. There is considerable reason for believing that an ultramicroscopic organism is responsible for this condition (See Foster, Journal of Infectious Diseases 21:451 [Nov.] 1917).

Second, there is no acceptable clinical evidence that vaccination with the influenza bacillus, the Strepto­coccus, the Pneumo­coccus or the Micro­coccus Catarrhalis will influence the course of an infection due to one or the other of these organisms. It has been repeatedly found that a staphylo­coccus vaccine is of a certain degree of value when the infection with the staphylo­coccus is localized, but it is well known that general systemic infections with the staphylo­coccus are not at all benefited.

Third, the letter submitted as evidence by the Mulford Company is not convincing. The Council is not prepared to accept evidence of this sort unless it is in volume large enough to justify a definite conclusion.

Holding that there is no evidence for the value of this mixture, the Council declared “Influenza Serobacterin Mixed-Mulford” inadmissible to New and Non­official Remedies because its use is illogical.

Sherman’s Mixed Vaccine No. 40

Because of inquiry received the Council decided to consider this preparation and requested the manufacturer, G. H. Sherman, Detroit, Mich., to submit evidence in support of the claims made for it.

This vaccine is said to be made from killed cultures of Strepto­coccus, Pneumo­coccus, Micro­coccus catarrhalis, Staphylo­coccus aureus, and Staphylo­coccus albus. In the printed matter sent out by G. H. Sherman this vaccine is recommended for hay-fever, in which it is stated that some of the symptoms are due to bacterial invasion of the respiratory mucosa; for tonsillitis, both as a remedy and as a prophylactic against rheumatic and other sequelae; for “throat infections”; for rhinitis with the claims that acute coryza can be aborted within twenty-four hours; for pneumonia in which it is advised for all stages; for laryngitis, for bronchitis, and for asthma.

No acceptable evidence was submitted as to the value of the product in the treatment of any of the foregoing conditions. In view of what is known about non-specific reactions, it seems likely that any influence which this vaccine may have on the diverse conditions enumerated by the manufacturer, is due to this, rather than to the combination of organisms used in its preparation.

On the recommendation of the Committee on Serums and Vaccines, the Council declared “Sherman’s Mixed Vaccine No. 40” ineligible to New and Non­official Remedies because the therapeutic claims made for it are unwarranted (Rule 6) and because the combination, in view of its complexity, is irrational and detrimental to sound therapy (Rule 10).—(From The Journal A. M. A., June 23, 1918.)