The path of vaccine development over the centuries has intertwined the relentlessness of infectious disease with the great advances of science. Here we share vaccine development milestones from Nature to navigate the breakthroughs in vaccine development.

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Nature: Vaccine Development
Timeline - 20 Major Milestones
As a public health emergency of international concern, the severe acute
respiratory syndrome coronavirus 2 (COVID-19) pandemic has resulted in
millions of confirmed cases and deaths worldwide.
The world is looking to the COVID-19 vaccine to mitigate the outbreak. With
several vaccines now available, a race to save lives has begun.
The path of vaccine development over the centuries has intertwined the
relentlessness of infectious disease with the great advances of science. Here we
share vaccine development milestones from Nature to navigate the
breakthroughs in vaccine development.
1798, Smallpox Eradicated Using
Cowpox
In the 18th century, smallpox was prevalent in Europe and caused a large
number of deaths. Reports circulated in England and elsewhere that having
contracted cowpox could prevent smallpox, and dairy workers generally did not
develop serious illnesses after exposure to smallpox.
The cowpox virus, a smallpox virus in cattle, can also infect humans. Edward
Jenner inoculated a boy, James Phipps, with material from a cowpox lesion,
formally testing the hypothesis that previous infection with cowpox could

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prevent smallpox. This led to the modern vaccination and eventual eradication
of smallpox in 1980.
1881, The first live attenuated vaccine
Pasteurella multocida is widespread in the respiratory and intestinal tracts of
many domestic and wild animals and can cause many serious infectious
diseases in animals. In 1877, Louis Pasteur began studying chicken cholera and
discovered that cultures of Pasteurella multocida lost virulence over time, which
he named "attenuation," and later collaborated on the development of a live
attenuated vaccine for Bacillus anthracis. The discovery and experimentation of
this vaccine led to the creation of several subsequent live attenuated vaccines,
such as rabies vaccine and BCG.
1890, Serum therapy
Emil von Behring and Shibasaburo Kitasato discovered that whole blood or
cell-free serum from rabbits previously injected with tetanus bacteria could
protect mice infected with lethal doses of tetanus bacteria. This landmark
discovery was later applied to serum therapy, where serum from a person who
had recovered from an infectious disease was transferred to a person who was
being infected with the same pathogen, and was first used to treat tetanus and
diphtheria. In 1901, the Nobel Prize in Physiology or Medicine was awarded to
Emil von Behring for his contribution to the development of serum therapy.
1921, BCG: the first tuberculosis
vaccine
Tuberculosis (TB) was considered incurable in the past. Scientists obtained
highly attenuated live strains of mycobacterium tuberculosis through extensive
passaging cultures and used this method to develop a live attenuated vaccine
for tuberculosis, BCG, which was used for the first time to protect high-risk
infants (healthy, but with TB in all dependents). Several subsequent neonatal
vaccination programs have demonstrated the safety and efficacy of BCG
vaccine.

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1926, Discovery of Alum Adjuvant
British immunologist Alexander Thomas Glenny observed that vaccines
developed using the aluminum salt precipitation method produced better
antibody responses in guinea pigs than soluble toxoids. Researchersrecognized
the immunostimulatory properties of aluminium salts and used alum to boost
the effectiveness of the diphtheria toxoid vaccine.
1937, development of 17D yellow fever
vaccine
In the 19th century, yellow fever spread around the world with the slave trade.
Today, yellow fever is preventable thanks to Max Theiler's research on the 17D
vaccine strain, which was licensed in 1938 and is well tolerated, provides 100 %
protection and lifetime protection with few serious side effects in a single dose.
In 1951, Theiler was awarded the Nobel Prize in Physiology or Medicine for
"discoveries concerning yellow fever and its prevention", the first and only
vaccine researcher to receive the Nobel Prize.
1939, The first effective whooping
cough vaccine
There are two vaccines against whooping cough, a whole-cell inactivated
vaccine, wP, developed in 1939, and an acellular vaccine, aP, developed in 1974.

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aP is less effective than wP. Both vaccines are imperfect, and although most
cases of whooping cough are controlled, rebound transmission occurs in stages,
and new vaccines are being developed.
1949, Poliovirus cultured in cells
Polio, or poliomyelitis, is a paralyzing disease caused by poliovirus infection. In
the 1940s, scientists discovered the ability to grow poliovirus in human cells in
laboratory media, which made possible the development of attenuated virus
strains and led to the successful development of the first polio vaccine. in 1954,
the Nobel Prize in Physiology or Medicine was awarded to John Franklin Enders,
Thomas Huckle Weller, and Frederick ChapmanRobbins for their contributions in
discovering the ability of poliovirus to grow in various tissue cultures.

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1955, defeating paralysing scourge
Paralysing scourge has now been eradicated in almost all but a few countries
where sanitation and health care infrastructure measures are lacking, thanks to
the development of two polio vaccines in the 1950s, an injectable inactivated
virus and an oral vaccine containing attenuated virus.
1979, the first recombinant DNA
vaccine for hepatitis B virus
The first hepatitis B virus (HBV) vaccine was also the first vaccine produced
using recombinant DNA technology to generate virus-like particles that elicited
an immune response comparable to that of the causative pathogen itself, and
showed the potential of this technology in vaccine development.
1981, smallpox was eradicated
In 1977, after 10 years of vaccination and containment, the last naturally
occurring case of smallpox appeared in Somalia, and in 1980, the WHO declared
the world free of naturally occurring smallpox virus.
1980, conjugate vaccine developed
Polysaccharide-coated bacteria can cause serious bacterial infections, among
which hemophilus influenzae type b (Hib) is the leading cause of bacterial
meningitis and pneumonia in children, resulting in a large number of child
deaths worldwide. Conjugate vaccines are the first novel protein polysaccharide
vaccines that enhance the immunogenicity of bacterial polysaccharides by
binding to a protein carrier to effectively prevent Hib infections.

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1984, non-specific effects of vaccines
were discovered
In the 1980s, researchers found through a series of studies that the beneficial
effects of measles vaccination on all-cause mortality could not be explained by
prophylaxis. These studies supported the idea of non-specific effects of vaccines,
i.e., that some live vaccines could produce protective effects unrelated to
specific protection.
1991, Hope for HPV Vaccine
A major obstacle to the manufacture of HPV vaccines was that HPV viruses could
not be grown in the laboratory and therefore could not be produced by the
commonly used method of attenuated or inactivated viruses. In 1991, a key
technological advance enabled scientists to create human papillomavirus (HPV)
virus-like particles in the laboratory that could eventually be used to generate
HPV vaccines that could prevent the development of HPV-associated cancers.
2000, Vaccinology in reverse
Two landmark papers in Science in 2000 jointly mapped the entire genome of
the MenB strain (MC58) that causes meningitis and used this genomic
information to identify a large number of novel surface-bound antigens. This led
to the birth of reverse vaccinology, a bottom-up approach to vaccine
development from the genome to the vaccine.
2006, Dendritic Cell Cancer Vaccine
Shows Efficacy
In multiple clinical trials of the sipuleucel-T vaccine in prostate cancer patients,
the vaccine showed benefits in median survival and induction of T-cell
responses. sipuleucel-T is a dendritic cell-based cancer vaccine that is
personalized for each patient. sipuleucel-T has since become the first dendritic
cell cancer vaccine approved for the treatment of advanced prostate cancer.

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2011, Rinderpest eradication
Rinderpest is a serious viral disease that affects cattle. A concerted global effort
controlled the spread of rinderpest and eventually eradicated it in the wild,
making rinderpest the 2nd disease to be eradicated primarily through vaccines.
2013, Synthetic Biology Accelerates
Vaccine Development
To speed up development, scientists used synthetic biology techniques to
devise a method for translating genetic sequence data from a novel virus into a
vaccine candidate. In developing a vaccine against a novel avian influenza virus,
developers used gene sequences downloaded from the Internet for a pandemic
influenza virus to chemically synthesize a vaccine within a week. They also
inserted the same gene sequence into a genomic backbone common to many
influenza viruses to form an inactivated viral vaccine, which entered human
testing in August 2013.
2017, individualized neoantigen
vaccines were born
Tumor cells originate from the body's own cells and retain most of their
endogenous proteins, so the fight against cancer requires finding new antigens
that are specifically expressed by tumor cells due to genetic mutations.

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A cancer vaccine developed using a complex and highly technically demanding
manufacturing process for mutated proteins in each patient's tumor has been
shown in trials to trigger a highly specific anti-tumor immune response in
melanoma patients.
2019, Ebola vaccine approved
The FDA approved the recombinant Ebola vaccine rVSV-ZEBOV for marketing.
An extensive ring vaccination in the Democratic Republic of Congo
demonstrated that this vaccine provides a high level of protection.
Conclusion: Race against COVID-19
Before the arrival of COVID-19, the fastest vaccine in human history, it also took
4 years to hit the market. Now with COVID-19 ravaging the world, scientists
have launched multiple vaccines in less than 1 year, which is already a major
victory in the history of human vaccine development. In addition to the vaccine,
COVID-19 drugs are also being developed. The virus and science are still at war,
and we look forward to more good news in the future.
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References:
[1] Nature Milestones in Vaccines
https://www.nature.com/immersive/d42859-020-00005-8/index.html