Prophylactic Vaccination Against Influenza
The hope of finding an early solution to the vaccine problem in influenza appeared to be in the development of a prophylactic “bacterial vaccine” similar to that which proved so efficient for typhoid. In his discussion of the vaccine problem in pneumonia, Fennel pointed out that, theoretically, any disease of microbic origin in which spontaneous recovery is at all possible should yield to specific prophylactic measures. The difficulty, however, of preparing a bacterial vaccine for influenza comparable to that for typhoid fever is that the unquestioned cause of influenza has yet to be determined. The probable cause of influenza is the Pfeiffer bacillus, but its relationship has not been proven beyond question. On the other hand, the innocence has likewise not been proven, as Dr. Holman in his article of this series has ably shown. It is not my intention to go deeply into the question of etiology, but simply to bring out a few points which a priori seemed to indicate that the reasonable solution of vaccine prophylaxis was in the preparation of a pure Pfeiffer bacillus suspension.
The experiments in man lead to very surprising results. Rosenau, Keegan, Goldberger and Lake, at Gallops Island, Boston, Mass., (1) inoculated volunteers with pure culture of B. Pfeiffer, with secretions of the upper air passages and with blood from typical cases of influenza. Sixteen men, of whom 13 were supposedly non-immune, had Pfeiffer bacilli installed into their nasal passages, and none of them developed the disease. Secretions filtered and unfiltered also gave negative results. Contact with well-developed early cases also failed. McCoy and Richey (1a) conducted similar experiments in San Francisco, with negative results. The men of the latter group had been vaccinated with a mixed streptococcic vaccine, which may have played some part. Had the experiments with the Pfeiffer bacillus been negative and the other experiments positive, they would have shown that the bacillus of Pfeiffer was not the cause of influenza; but since all attempts were negative, it merely brought out the fact that there had been a change, due probably to some immune factor, which seemed to have acted alike on the Pfeiffer bacillus and all other types of virus present, and to have made them all innocuous. These experiments still leave the cause of influenza in question.
Those who are opposed to the Pfeiffer bacillus being the cause of influenza in its epidemic form base their position on the points that the common finding of the bacillus might be accounted for on the grounds of its being a secondary rather than a primary invader; that while it is not so common at ordinary times, it does occur with other organisms in whooping cough and sometimes in chronic diseases of the air passages, and that the rules of Koch have not been complied with in that the organism has not been found in every case of the disease; that where it has been grown in pure culture and inoculated into man and animals, it has either produced no disease, or the lesions which followed have not been typical of epidemic influenza. On the side of those who believe that the Pfeiffer bacillus is the chief cause, or, at any rate, that it is partly responsible for epidemic influenza, are the facts of its fairly constant presence in the purulent bronchial secretion of patients suffering from epidemic influenza; its relatively uncommon occurrence at other times; its known pathogenicity in occasional cases of meningitis, and in the inflammation of the bony sinuses of the head and face; the relative immunity of nearly all common laboratory animals and the fact that the attempts to transfer epidemic influenza from man to man failed not only when Pfeiffer bacilli were used, but also when direct contact and direct coughing by the patient into the face of the volunteer were tried. The argument that many cantonment laboratories failed to find the organisms loses weight when we find that the percentage of positives increased where the material examined was removed directly from the lungs at autopsy, where special cultural methods were in use and where the laboratory personnel was large enough to devote a sufficient amount of time to each individual culture. All of these points indicate that the organism was overlooked in a great many instances. In our laboratory we found the examination of sputa very unsatisfactory because of the great amount of contamination, and because the bacillus seemed to lose its ability to grow after a relatively short time in the sputum in vitro. Moreover, I am convinced that the bacillus changes its morphology to such an extent under varying conditions as to make it impossible of identification when present among other organisms in sputum smears. The failure of animal inoculations is also not conclusive evidence against the Pfeiffer organism, because guinea pigs, rats and mice have a natural immunity for them. Rabbits are only slightly susceptible, and then only to intravenous injections. The mixture of the Pfeiffer bacillus with any one of several other pathogenic organisms will increase the pathogenicity of both. Monkeys inoculated intracranially develop a typical Pfeiffer bacillus meningitis.
Whatever the ultimate outcome of the investigations as to the parasitic cause of epidemic influenza, the Pfeiffer bacillus was the generally accepted cause at the beginning of the 1918 epidemic, though it was at once realized that most of the deaths were due to complicating pneumonias and to secondary infections with other organisms. Under the circumstances, one of two courses was open: (a) the acceptance of the Pfeiffer bacillus as the presumptive cause of influenza and the preparation of a specific prophylactic vaccine against infections with that organism; or (b) the use of a mixed bacterial vaccine containing the common and most deadly secondary infecting organisms, designed to increase the patient’s general resistance by decreasing his susceptibility to the allied, collateral and secondary infecting agents. Attempts were made along both lines, with more or less unsatisfactory results.
The Attempt to Develop a Specific Prophylactic Vaccine by the Use of Pure Pfeiffer Strains
By a specific prophylactic vaccine for any given disease, we mean a material which when inoculated into an individual will actively protect that individual against the given disease. In infectious diseases, the immunizing material is usually of microparasitic origin (in contrast to desensitizing substances used in pollen diseases and those due to unusual sensitiveness to foreign proteins), and is specific only for the disease caused by the microparasite from which the material was prepared. With the knowledge in hand during the epidemic, the logical plan seemed to be to prepare a pure Pfeiffer bacillus vaccine, the object of which was to eliminate primary infection with that organism and thus prevent the secondary invaders from obtaining a fertile soil.
While specific Pfeiffer bacillus vaccines had been tried in treatment, the field was a comparatively new one so far as prevention was concerned. Many of the biological products companies had so-called influenza vaccines on the market for treatment purposes, and many of these contained Pfeiffer bacilli. A few preparations of pure strains of the bacilli were also available, but I was unable to find any records of their use for prophylaxis. Lacy (2) reported two cases of sinusitis treated with autogenous vaccines made from pure Pfeiffer strains—one patient improved rapidly and the other showed no change. Investigation of several of the other references on influenza vaccines showed that mixed vaccines had been used in each instance. The work of Flexner and Wolstein (3, 4 and 5) indicated that active immunizing substances could be prepared from the Pfeiffer bacillus, although they worked with serum instead of vaccines. They prepared an anti-influenza-meningitis serum by immunizing goats and horses. These sera cured monkeys of experimentally produced influenzal meningitis. The sera showed agglutinins and bacteriotropins for Pfeiffer bacilli, as well as positive fixation tests in dilutions of 1 in 100, but they contained no lysins. The serum was offered for intradural use in treating influenzal meningitis, but was found to have no value when used in human cases.
The first references which we have found on the use of pure Pfeiffer bacillus vaccines for the prevention of epidemic influenza were those of Leary (6), (7), and of Rosenau (8). Shortly after the appearance of the first influenza cases in Boston, Leary used a vaccine prepared from several strains of Pfeiffer bacilli both for the treatment of influenza and for its prevention. The vaccine for the latter purpose was given to medical students and nurses, and the first results were apparently very encouraging. Continued use has not been convincing. Barnes (9) reported an attempt to protect the employees and patients of an institution near Woonsocket. On October 9 a case of influenza developed in the female ward, and was followed five days later by another. On October 22 the disease appeared in the male ward, and the same day 172 employees and patients were given their first inoculation with Leary’s vaccine. Doses of 400, 800 and 1,200 million bacilli were given at 24–hour intervals. All persons who had developed influenza before the three doses had been completed were excluded from the computation of the disease incidence, which was found to be 20 per cent. both among vaccinated and unvaccinated individuals. The mortality rate was 16 per cent. for the 25 cases among the vaccinated, and 15.8 per cent. among 57 unvaccinated patients. The result failed to show any protective qualities for the vaccine.
The best controlled vaccine experiment in which Leary’s vaccine was used was that reported by Hinton and Kane (10), and was carried out at the Monson State Hospital for epileptics. The hospital had a population of 979 inmates, ranging from 4 years of age to senility; of these 461 were vaccinated and 518 were not. Vaccination was begun on October 6, and three doses of 400, 800 and 1,200 million were given at 24–hour intervals. The first case of influenza developed a few hours after vaccination was completed, but there were no more cases before October 12, when five cases developed. The table shows the result of the work, and that the vaccine failed to protect.