A newly found handbook for developing vaccines during World War II in China: the legacy of global responses to crises.

The August this year marks the 75th anniversary of the ending of World War II (WWII), which is the largest and most destructive war in modern world history, with an estimated 80 million people or about 3% of the world population died. However, epidemiologically the WWII also played a key role in spurring the vaccine innovation [1]. In the past, wars often caused the spread of infectious diseases like new waves of emerging infections, but only worse than the outbreaks of Ebola and the more recent COVID-19 in modern time because multiple pathogens could be involved during the wartime. The US military recognized during the WWII that infectious diseases are not less threatening than enemies in the battlefield, and forged with industry and academia to develop vaccines for the soldiers. The efforts also led to formal wide use of vaccines to global general populations after the war.

Almost completely unknown to the world scientific community, microbiologists in China had very formidable efforts in the development of vaccine and bioproducts in the early 1940s during the WWII. A recent discovery of a completely handwritten and high quality 105-page handbook of vaccine manual from two former researchers, late Professors Bin Ni and Bingqing Xu, brought back the direct evidence and the scope of vaccine work exactly 80 years ago in China during the WWII (Figure 1).

Figure 1.

A newly found 105-page handwriting notebook (19 × 13 cm in size) documenting efforts in developing bio-products or vaccines 80 years ago in China: (a) cover page of this notebook; (b) and (c) table of contents of the handbook; (d) the page describing typhus vaccine; (e) the page describing diagnostic serum; (f) the page illustrating day 9 and day 12 aged chicken embryos for producing cholera and smallpox vaccines, respectively; (g) the recalling note about this handbook by the first author Prof. Bin Ni on February 24, 1992; and (h) late Professors Bin Ni and Bingqing Xu in 1946.

Profs Ni and Xu, both born in 1917 and later as a married couple, were junior faculty members of the early days of Nanjing Medical University (NMU). Like many universities in China at that time, NMU (under a different name at the time) moved to the western inland of country to escape from the Japanese invasion and occupation. Despite woeful shortage of resources, NMU established a new Chinese Institute of Preventive Medicine. Under the leadership of the late Prof. Meixian Wang [2], NMU scientists worked hard to develop a wide variety of much needed vaccines (Table 1).

Table 1.

Bio-products categorized by their purposes in the handbook

Prevention	Treatment	Diagnosis
Pathogen Vaccines	Antisera and Bacterin	Toxin and Sera
Bacterium	Bacterin	Toxin
cholera vaccine	diphtheria antiserum	diphtheria Schick reaction
typhoid vaccine	tetanus antiserum	scarlet fever Dick-serum
paratyphoid vaccine	meningitis antiserum	old tuberculin
cholera-typhoid mix vaccine	pneumonia antiserum	bacterial liquid coagulase test
red dysentery vaccine	scarlet fever antiserum	mallein
plague vaccine	erysipelas antiserum	Sera
pertussis vaccine	Antisera	various diagnostic sera
gonorrhea vaccine	rabies antiserum
staphylococcal vaccine
streptococcus vaccine
pneumococcal vaccine
influenza bacillus vaccine
meningococcus vaccine
Virus
cowpox vaccine
rabies vaccine
Toxoid Vaccines
diphtheria toxoid
tetanus toxoid
scarlet fever toxoid
red dysentery toxoid

As stated by an additional single page recalling note written in 1992 by Prof. Bin Ni, this compiled manual of bio-products was rediscovered as a historical research document, and now it has been evaluated for its academic and scientific values by a group of international experts of epidemiology and immunology. The list of bioproducts included in the manual is quite impressive and comprehensive, including active vaccines for typhoid fever, rabies, smallpox and cholera, and passive antisera like tetanus antitoxin and diphtheria antitoxin (Table 1).

Detailed step-by-step protocols are documented in this neatly written manual (Figure 1), including the type and amount of reagents needed and the instructions on how to prepare such biological products. The in vivo procedures are also well described with exquisite diagrams as part of the guidance. This handbook was produced during 1940–1941, clearly serving as a source of lab instructions and guidelines for the work conducted in NMU’s Chinese Institute of Preventive Medicine. There was no confirmation on whether any vaccine or antiserum products were actually used in humans or animals to prevent infections as implied from the recalling note. Nor is known from where the original scientific contents were received.

The vaccine manual is now donated to the NMU history museum, Nanjing, China, by Profs Ni and Xu’s surviving children including the corresponding author of this paper. It provides great value to have a close look at the actual work of developing vaccines during the WWII time. Such information is scarce even in the scientific literature in the US and other Western countries. As highlighted by a recent New England Journal of Medicine commentary [3], the urgency, aura of crisis, national attention, and material resources needed during a wartime have catalyzed developments in medicine which should also include vaccines. We can only hope the COVID-19 pandemic, no less damaging than a world war to some degree, will also stimulate the development of better vaccines to control the current and future emerging infections, just like what were accomplished after the WWII.