Edward Jenner, a physician working in rural England, has been credited with the 'discovery' of vaccines. In the late 18 th century, Jenner became aware that milkmaids who had been infected with cowpox were subsequently immune to smallpox, a disease associated with a high case-fatality rate and grossly disfiguring sequelae among survivors. He inoculated a young boy with matter from a cowpox sore on the hand of a milkmaid, and his resultant immunity to smallpox became the first scientifically documented vaccination. However, the process of violation -smearing a tear in the skin with cowpox to confer immunity to smallpox -had been practiced in China since the 17 th century [1] . In the ensuing 200 or so years, systematic implementation of smallpox vaccination programs culminated in the World Health Assembly declaring the world free from smallpox in 1980 [2] .
In 1885, Louis Pasteur and Emile Roux developed the rabies vaccine. They pioneered the science of attenuation by allowing infectious tissue to dry for up 10 days before inoculating their subjects with repeated doses of increasing virulence. A similar process was applied to the development of live-attenuated cholera and anthrax vaccines. During the first half of immunity (Th2 response). This physiological adaptation enables the semi-allogenic fetus to be protected from immunologic rejection, but these adaptive changes render pregnant women more susceptible to severe disease. The risk to pregnant women from respiratory viruses is further compounded by physiological cardio-respiratory adaptations, leading to a higher risk of morbidity and mortality among pregnant women diagnosed with pneumonia [5] .
The disproportionate impact of influenza on pregnant women is evident from the earliest recorded pandemics. The 'Spanish flu' pandemic of 1918, resulted in an estimated 50 to 100 million deaths globally, but the mortality rate among pregnant women was disproportionately high. A survey of medical practitioners in the United States reported a case-fatality rate of 27% among 1350 pregnant women with influenza: all the reported deaths occurred among the 678 cases complicated by pneumonia [6] . A study from Chicago reported a mortality rate of 45% in pregnant women admitted with influenza complicated by pneumonia, compared to 32% among 2053 non-pregnant patients admitted with the same illness over a 7-week period [7] [14, 15] . Further discoveries of influenza subtypes led to the introduction of bivalent and trivalent vaccines. Given that influenza in pregnant women was known to result in more severe outcomes, the United States public health authorities recommended in 1960 that pregnant women should be prioritised to receive the (now widely available) inactivated influenza vaccine [16] . However, it was not until 1997 that the 35] . Furthermore, the presence of virus in placental specimens of women who had received the vaccine raised concern regarding teratogenic potential of the vaccine [36] .
The rubella vaccination strategy adopted in the United States aimed to eradicate the reservoir of the virus in childhood, thereby reducing the risk of rubella infection and the likelihood that pregnant women would be exposed. This was achieved through vaccination programs that included all children aged from 1 year and up to puberty. The populationbased vaccination program was successful in preventing epidemics, leading to dramatic reductions in the rates of rubella infection in pregnancy, and subsequently congenital rubella syndrome, over the ensuing 25 years [37] .
The United Kingdom adopted an alternative approach by vaccinating adolescent girls between the ages of 11 and 14 years, proposing that girls immunised earlier in life might have declining levels of antibodies over time, making them susceptible to rubella infection again by their childbearing years. In the UK, boys were excluded from the vaccination policy. Seronegative pregnant women received the rubella vaccine post-partum. However, the incidence of rubella infection in young children remained unchanged, and cases of congenital rubella infection persisted [38, 39] . This led to a change in policy in 1988, when the measles, mumps, rubella (MMR) vaccine was recommended for all children, boys and girls, aged 1 to 2 years. Subsequently, repeated doses of the MMR vaccine were recommended for children at 4 to 5 years of age, and before entering puberty. This resulted J o u r n a l P r e -p r o o f in herd immunity and a predictable reduction in cases of rubella infection in children, and reported cases of congenital rubella syndrome [40, 41] .
At present, in most countries, the schedule for rubella vaccination is two doses before 24 months of age [42] . Furthermore, many developed nations routinely screen women of childbearing age for rubella antibodies to identify and vaccinate seronegative individuals.
No cases of congenital rubella syndrome have been reported in women receiving the vaccine peri-conceptually or in pregnancy. Nevertheless, due to the theoretical teratogenic risk of the live-attenuated rubella vaccine, it is recommended not to vaccinate during pregnancy, and if given preconceptually, to delay pregnancy for 28 days following vaccination [43, 44] . Vaccination in pregnancy can thus confer valuable passive protection to the newborn. As early as 1879, it was recognised that infants born to women who had received the smallpox vaccine during pregnancy were immune to the virus in early life [49] . The vaccine-induced antibody response results in transplacental passage of the immunoglobulin to the fetus, conferring passive immunity to the fetus and newborn [50] . Maternal vaccination programs for tetanus and pertussis provide protection to the newborn infant against these vaccinepreventable diseases for up to 6 months after birth, the time when the infant's own immune system becomes capable of mounting a mature immune response to vaccines.
Tetanus immunisation, and more recently pertussis vaccination, are examples of vaccinations administered in pregnancy largely for the benefit of the newborn. Although the J o u r n a l P r e -p r o o f prevalence of tetanus has dramatically decreased around the world, neonatal tetanus remains a preventable cause of death in many developing countries. Neonatal tetanus is caused by contamination of wounds with the spores from Clostridium tetani. In the developing world, this is mostly through contamination of the umbilical cord stump due to unsanitary birth practices. The affected infant presents with an acute loss of the ability to suck, generalised rigidity, and muscle spasms. In the absence of medical treatment, the case-fatality rate approaches 100%. Even with hospital care, including the availability of intensive care, between 10 and 60% of affected infants die [51] .
The tetanus vaccine was first licensed for use in 1938, and widely administered during the Second World War. During the 1960s observational studies demonstrated that use of two or more doses of tetanus toxoid during pregnancy could prevent neonatal tetanus [52] . A double-blind trial involving 1618 women was subsequently conducted in Columbia, where the neonatal tetanus mortality rate was estimated at 11.8/100. These women were [65] . A further epidemic occurred in 2010 in California where the incidence of pertussis in infants under 6 months of age reached 435 per 100,000 and 10 infants died. Nine of the deaths were in previously healthy infants, younger than 2 months of age, who had not yet been fully vaccinated against pertussis [66] .
This pattern was reported in other high-income countries. A national increase in pertussis cases was reported in the United Kingdom in late 2011, initially observed in adolescents and young adults but later reported in young infants [67] . In 2012, there were 14 deaths in infants with confirmed pertussis in the UK [68] . The reduction in infant morbidity and mortality from both tetanus and pertussis is testament to the value of antenatal immunisation for the benefit of the newborn. The success of pertussis vaccination can be attributed to the collection of epidemiological data that identified young infants as being at greatest risk, and large cohort studies demonstrating vaccine safety, thus improving uptake. The prevention of neonatal tetanus has been achieved through early clinical trials that confirmed efficacy, and informed optimal dosing strategies, as well as successful global public health campaigns, such as the World Health Organisation's Maternal and Neonatal Tetanus Elimination initiative.
What messages does history have for pregnant women, and those caring for them, in the current COVID-19 pandemic? Health crises across history have accelerated vaccine discovery and development, and the COVID-19 pandemic is no exception. At last report, there were 29 candidate vaccines to novel coronavirus (SARS-CoV-2) in clinical evaluation worldwide [74] . Many of these are entering Phase 3 trials and, if efficacy is proven, J o u r n a l P r e -p r o o f potentially be available by early 2021. As the world eagerly awaits an effective vaccine, the pandemics of history offer some valuable insights that will inform vaccine development and uptake in pregnant populations. They have highlighted the value of international collaborative surveillance systems to identify risks uniquely or disproportionately faced by pregnant women, the imperative for pregnant women to be included in clinical trials, the value of registries to document current and future adverse health outcomes of mothers and their newborns, the need for a continuing audit cycle and the critical importance of community engagement to ensure that both public health messages and effective vaccines are met with widespread uptake.
The development and uptake of vaccines has been driven by public health crises across many decades. The demonstrated improvements in maternal and perinatal outcomes in both remote and recent history mean that vaccinations prior to or during pregnancy have earned their place as public health care imperatives. The disproportionate morbidity and mortality shouldered by pregnant women during influenza pandemics has led to them being targeted for vaccination each flu season. The devastation brought by rubella epidemics spurred the development of a vaccine, which ameliorated the teratogenic impact of this viral infection. The immunity passed from mother to infant following vaccination for pertussis and tetanus ensures protection of the newborn in the early weeks of life, making enormous inroads into reducing preventable deaths globally. Vaccination prior to conception and during pregnancy is a vital public health measure to reduce preventable mortality and morbidity for the mother, fetus and infant. • The benefits of passive immunity for tetanus and pertussis have resulted in significant reduction in infant mortality and morbidity due to optimal timing and dosing during pregnancy
• Ensure that pregnant women are afforded the same autonomy as other adults to participate in clinical trials of vaccines and therapies for emerging pathogens
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