By Raina MacIntyre
October 4 2014
Vaccines are one of the greatest public health achievements in history. In 1796 Edward Jenner discovered that inoculation with cowpox could protect against smallpox. The term “vaccinus” means “Of a cow” in Latin, and refers to Jenner’s discovery. Smallpox vaccine was followed in the 19th century by vaccines against plague, diphtheria and typhoid. Smallpox vaccine was used to eradicate smallpox from the world, with the last naturally occurring case documented in 1977. Mass immunization programs as a public health measure to control infectious diseases began in the 1930s (diphtheria), and the public health implementation of vaccine programs developed and matured over the next 50 years with infant and school-based programs for diphtheria, tetanus and pertussis. Vaccine technologies vary from live attenuated virus vaccines (such as MMR - measles, mumps, rubella) to inactivated antigens (such as DTP), all of which aim to mimic the response to natural infection (without causing illness) and thereby confer immunity to disease.
Today, EPI programs(1) in developing countries include measles, mumps, rubella, DTP, polio and hepatitis B. In developed countries, other more expensive vaccines such as pneumococcal conjugates, meningococcal C conjugate, HPV and rotavirus vaccines are included in national immunization programs. Infectious diseases were once the leading cause of death and disease in the world, but vaccination programs have led to the control of many of these diseases. In developed countries, in addition to infant immunization, adult immunization is included in funded vaccine programs, but remains less developed as a public health measure for disease control despite ageing populations.(2) In addition to routine population vaccination programs, some vaccines are targeted for at-risk sub-groups. An example is the vaccine for Japanese Encephalitis, which has a significant side effect profile and so is reserved for people in endemic areas who are at high risk for JE. Travellers, health care workers and immunocompromised people are other groups who have targeted vaccine recommendations based on increased risk.
It has been pointed out that vaccine development is driven by potential for profit, and so disproportionately favours the diseases and concerns of wealthy countries. For example, Ebola vaccines have been in development prior to the current West African epidemic, but have not been a priority. (3) At least 3 companies are currently developing vaccines against Ebola, including GSK, Johnson and Johnson with Bavarian Nordic, and Inovio(4). The GSK vaccine uses a chimpanzee adenovirus vector containing Ebola genes. It is not expected that population vaccination programs will be available until late 2015 to 2016. So what does this mean for the potential to stop the epidemic of Ebola using vaccines?
Central to disease control with vaccines is the concept of the basic reproductive number, R0. The R0 is the number of secondary cases that arises from an infectious case in an immunologically naïve population. For example, if one person with measles infects on average 15 other people, then the R0 of measles is 15. R0 depends on characteristics of the organism, the host and the population. In general, R0 is higher in more densely populated areas than remote, rural areas because of higher mixing between people. The higher the R0, the more difficult it is to eliminate or eradicate a disease. Elimination refers to removing endemic transmission within a given country, and eradication refers to global removal of the disease. To be eradicable, generally a disease must have a moderate R0, and must only have a human host. Diseases which have human and animal hosts are much harder to eradicate, because infections can continue to be introduced to humans from an animal reservoir. Smallpox, for instance, was eradicable because it had no animal reservoir, and a moderate R0, estimated to be about 3-6 at the time it was endemic in the world.(5) This is much lower than the estimated R0 of measles, which whilst it does not have an animal host (and so is theoretically eradicable) has a R0 of about 12-18.(6) This means that eradicating measles will be a much greater public health challenge than smallpox. The concept of R is related to herd immunity, which is the required proportion of the population which must be immune (either from infection or vaccination) in order to stop transmission of the disease. For smallpox, for instance, with a lower R0, vaccination programs needed to achieve immunity in about 60% of the population to eradicate the disease. In contrast, for measles, immunity must be achieved in more than 90% of the global population to eradicate the infection. The mathematical equation for calculating the required herd immunity (H) is: H = 1-1/R0. (7)
So, this is good news for Ebola in terms of the potential for vaccines to contain the epidemic. The estimates of R0 for Ebola in the current West African epidemic have been remarkably consistent at about 1.5-2.(8-11) Using the herd immunity equation and the higher estimate of R0 of 2 then, the required herd immunity is 1-1/2 = 0.5 or 50%. This is much lower than smallpox and measles, and translates to a required vaccine efficacy of around 50% if everyone who needs to be vaccinated is vaccinated and there are minimal vaccine failures. Achieving a population immunity of 50%, however, is not simply a function of vaccine efficacy. It also depends on vaccine coverage (the proportion of susceptible people who receive the vaccine), and on maintaining the cold chain to ensure that vaccines are not inactivated by poor storage. These will all be challenges in West Africa. In a practical sense, this means an Ebola vaccine should ideally have a clinical efficacy of at least 60% (to allow for less than optimal coverage and cold chain failures). In vaccinology, we are used to vaccines with very high efficacy, often in excess of 90%. In the case of Ebola, a vaccine with much lower efficacy than this, even 50-60% efficacy, will be good enough to achieve population control of the disease. Ebola is unlikely to be eradicable, because it has an animal reservoir and could continue to cause sporadic disease or outbreaks as it has done since it was discovered in 1976. However, the availablity of a vaccine which can be used in at-risk populations such as in West and Central Africa and also in health care workers and other front-line responders, is likely to have a major population health impact. It will also contribute to the occupational health and safety of health workers and front-line responders, which will strengthen disease control efforts considerably.
In the immediate future, however, other disease control efforts using other strategies (see https://sphcm.med.unsw.edu.au/infectious-diseases-blog/articulating-clear-strategy-ebola-control-turning-modeling-research-action ) must be stepped up to contain the epidemic, as the projected growth of the epidemic (11) will far outpace the availability of vaccines. This is a similar situation to pandemic influenza, where matched vaccines are not available in the early phases, and other measures such as anti-virals and non-pharmaceutical measures are critical in the early phase. The fact that Ebola vaccines are not yet proven in phase 3 clinical trials, as well as the far higher case fatality rate of Ebola, means the situation is more urgent for this epidemic than for pandemic influenza. We cannot afford to wait 1-2 years for population vaccine programs as the panacea, but must focus on other available control efforts such as increasing the proportion of patients in Ebola treatment units as outlined in my previous blog. This is a global catasrophe in which we are all stakeholders, and needs coordinated global commitment urgently.
Raina MacIntyre is Professor of Infectious Diseases Epidemiology at UNSW Australia and a senior research fellow at the National Centre for Immunisation Research and Surveillance. She led a major national collaboration in mathematical modeling of infectious diseases from 2005-2009, and has worked in vaccinology for over 15 years and leads a NHMRC Centre for Research Excellence in Immunisation. She won the Public Health Association of Australia National Immunisation Achievement Award in 2014.
Research profile: http://research.unsw.edu.au/people/professor-raina-macintyre
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