Efficacy of Whole-Cell Killed Bacterial Vaccines in Preventing Pneumonia and Death during the 1918 Influenza Pandemic

The 1918 influenza pandemic caused an estimated 20–100 million deaths worldwide [1]. There is growing epidemiologic, clinical, and pathologic evidence that the majority of deaths in this pandemic resulted directly from secondary bacterial pneumonia [2–5]. In the 1918 pandemic, Streptococcus pneumoniae was the predominant organism isolated from antemortem cultures from normally sterile sites in patients with influenza-associated pneumonia, followed by hemolytic streptococci, presumably representing Streptococcus pyogenes [4, 5]. The etiology of influenza was unknown at the time of the 1918 pandemic. Many contemporaneous investigators erroneously believed that bacteria, in particular Bacillus influenzae (Pfeiffer's bacillus, now known as Haemophilus influenzae) was the cause of influenza [6]. It was also generally believed, however, that most 1918 pandemic influenza deaths resulted from secondary bacterial pneumonia following primary influenza infections of whatever cause [2]. In attempts to prevent the primary disease of influenza, to reduce pneumonia and mortality, and to investigate the etiology of influenza, many bacterial vaccines were produced, tested, and administered during the 1918 pandemic. Here we review studies of whole-cell bacterial vaccines administered to healthy subjects during the 1918 pandemic to examine their efficacy in preventing influenza-associated pneumonia and mortality. An important concern about such a review is that the scientific quality of 1918 vaccine studies was low by today's standards, owing to such methodological flaws as lack of subject randomization. Moreover, whereas most vaccinations were given during the declining phase of the pandemic (fall-winter 1918–1919), the incidences of influenza, influenza-associated pneumonia, and deaths in vaccinated individuals were usually compared with the same outcomes in unvaccinated individuals from the beginning of the epidemic [6, 7], introducing unequal observation periods more favorable to vaccinated individuals. In addition, vaccinated individuals might come from select populations with reduced exposure or susceptibility to influenza because they had not had influenza between the appearance of the pandemic and the start of vaccination. Not fully appreciating such potential design flaws, investigators studying bacterial vaccines often believed that they had demonstrated a reduction in the incidence of influenza, which is not consistent with our understanding of influenza etiology. We reasoned that any true effect of bacterial vaccines on influenza disease might more plausibly result from reduced attack rates of secondary bacterial pneumonias and consequent reduced case fatality rates among patients with influenza. To examine this possibility while addressing methodological flaws of the original studies, we reanalyzed published data, asking whether vaccinated patients who developed influenza had lower attack rates of pneumonia or lower case fatality rates than unvaccinated patients with influenza. This approach should diminish bias caused by unequal observation periods, because these measures were less likely to be influenced by changing influenza incidence during the progress of the pandemic. In addition, the attack rate of pneumonia and case fatality rates among patients with influenza seems to be higher in the later phase of influenza epidemics [8–10]. Therefore, this approach may result in more conservative estimates of vaccine efficacy (VE), because the vaccinated individuals were more likely to be from the later phase of the 1918 pandemic.