The last naturally-acquired case of the variola major was identified in Bangladesh in late The last case of illness caused by the less virulent strain variola minor occurred in Somalia in Although the significance of this event may be under appreciated, it stands as one of the greatest accomplishments of the 20th century, if not one of the greatest human accomplishments of all time. Several factors unique to smallpox contributed to the success of this effort, including easily-diagnosed clinical disease, lack of subclinical infections, absence of transmission during prodrome, and lack of an animal reservoir.
In , the World Health Organization requested that all laboratories with smallpox virus either destroy the virus or submit their stocks to one of two collaborating centers in the United States Centers for Disease Control or the Soviet Union Moscow Institute. Most laboratories complied, but there is evidence that smallpox was subsequently developed as a biological weapon in the Soviet Union.
There have also been allegations that Russia has developed recombinant strains of smallpox with increased virulence and infectivity. The most widely used virus for smallpox inoculation has been vaccinia, which belongs to the genus Orthopoxvirus along with variola virus. Other species of Orthopoxvirus include cowpox the virus used by Jenner , monkeypox, and camelpox, among others. Vaccinia is a double-stranded DNA virus with a wide host range.
Its origin is uncertain, and there are many strains of vaccinia with different biological properties. Production of this vaccine was discontinued in The National Pharmaceutical Stockpile also includes the Aventis Pasteur vaccine, which was also manufactured from calf lymph. Multiple other strains of vaccinia have been used in other regions the world. Long-term research is underway using recombinant DNA technology to develop a safer vaccine that will provide an effective immune response without replication of vaccinia virus.
Both use the NYCBOH strain of vaccinia virus, but one is cultured from human embryonic lung cell culture and the other uses African green monkey vero cells. Clinical trials are underway. Until a new vaccine is licensed by the U. Food and Drug Administration, existing doses of Dryvax can be diluted and still generate an adequate immune response if the number of required vaccinations exceeds the number of doses in the national stockpile.
Smallpox vaccine is administered by puncturing the skin multiple times with a bifurcated needle containing a small quantity of vaccine. A small papule develops after 3 to 5 days, following the virus replication in the dermis. The papule evolves into a vesicular and pustular stage over 8 to 10 days. This is followed by scab formation with development of a residual scar.
The take is considered equivocal if a pustule, ulcer, or scab, does not develop at the vaccine site; revaccination is recommended in this situation. Smallpox vaccine is less safe than other vaccines routinely used today.
The vaccine is associated with known adverse effects that range from mild to severe. Mild vaccine reactions include formation of satellite lesions, fever, muscle aches, regional lymphadenopathy, fatigue, headache, nausea, rashes, and soreness at the vaccination site.
Inadvertent inoculation is the most common adverse event associated with smallpox vaccination. It occurred at a rate of per million vaccinations in a study.
VIG can be considered for use in patients with severe ocular vaccinia, but it may increase the risk of corneal scarring. Progressive vaccinia a. Eczema vaccinatum is a cutaneous dissemination of vaccinia virus that usually occurs in persons with pre-existing skin disease. It is typically mild and self-limited, but it may be severe or fatal, especially in young children. Death is usually caused by extensive viral dissemination, fluid and electrolyte imbalance, and bacterial sepsis. Post-vaccinial encephalitis is a rare adverse event that frequently leads to death, especially in infants and young children.
Generalized vaccinia results from blood-borne dissemination of vaccinia virus. VIG can be administered to speed recovery. Persons with atopic dermatitis or eczema, irrespective of disease severity or activity, are at risk of developing eczema vaccinatum and should not receive pre-exposure smallpox vaccination. Persons with incompetent immune systems are at risk of complications following smallpox vaccination. This group includes persons who are immunocompromised due to a specific illness e.
Infants less than one year of age should not be vaccinated because several studies have demonstrated that they are at increased risk of death and other complications. Vaccinia virus may be spread from person-to-person, which means that people who have close contact with recent vaccinees may be exposed to the virus and may be at risk of developing complications. For this reason, pre-exposure smallpox vaccination is contraindicated in persons who have close contact with individuals who have some of the risk factors described above.
Individuals should not be vaccinated if they have close contact with pregnant women or infants. Close contacts include both household members and sexual partners. Eczema vaccinatum and inadvertent inoculation are the most frequently reported conditions in contacts of recent vaccinees. Twenty percent of the eczema vaccinatum and inadvertent inoculation cases reported in a study occurred in contacts of vaccinees. Most cases of contact vaccinia occur through direct person-to-person transfer of virus.
The Advisory Committee on Immunization Practices ACIP began serious discussions about the risks and benefits of pre-event smallpox vaccination in Recently developed rotavirus vaccines provide a good example of this principle. Both widely used rotavirus vaccines cause the serious condition of intussusception in a small proportion of vaccine recipients, perhaps one to five additional episodes per vaccines, an acceptable risk considering the major reduction in hospital admissions and deaths achieved with these vaccines [ 21 ].
The issue of true vaccine side effects needs to be separated from incorrect claims such as the reported association between MMR vaccine and autism [ 14 ], and such false claims vigorously rebutted. In , the World Health Assembly made a decision to support the eradication of poliomyelitis with an initial target date of One of the three serotypes of polio virus type 2 has been eradicated, and this is probably also the case for serotype 3, but serotype 1 has proved more stubborn and this virus continues to circulate in three countries Nigeria, Pakistan and Afghanistan with periodic spread to other countries including Chad, Somalia and recently Syria figure 3 [ 22 ].
Nevertheless, there has been a Reaching the final goal of eradication of the last polio virus faces a number of challenges—technical, financial and social. Routinely used oral polio vaccines contain viruses belonging to each of the three serotypes and this can lead to an unbalanced immune response directed predominantly at one or two of the serotypes. This problem has been overcome by the development and deployment of bivalent and monovalent serotype 1 vaccines.
The polio eradication programme has been expensive, both financially and in the use of scarce human resources. Currently, there are no signs of a lack of intent among the international donors to pursue the campaign through to a successful conclusion but expenditure on a single infection at this level could not be sustained indefinitely.
Finally, there is the challenge of resistance to vaccination in some countries, especially Nigeria and Pakistan, where this has been sufficiently extreme to lead to the murder of health workers. It would be a tragedy if the polio eradication campaign failed at this point, not only because of the resurgence in cases that would inevitably follow, but also because of the negative effect that this might have on international support for global health issues overall.
Recent success in eliminating all wild polio viruses from India provides grounds for optimism. If the wild virus is eradicated successfully in or , then a decision will be needed on when to stop immunization with oral polio vaccine virus which can, very rarely, mutate to a more virulent virus causing paralysis. Some countries may decide to use the more expensive killed polio vaccine for a few years until all vaccine type polio viruses have disappeared [ 23 ]. Cases of paralytic poliomyelitis in www.
Uptake of these vaccines in the developing world has generally been slow despite their proven efficacy and a high burden from many of the diseases that they could prevent. Uptake of hepatitis B vaccine into the routine EPI of developing countries in Africa and Asia took over 20 years, despite the fact that the hepatitis B virus is a major cause of liver cancer in many parts of sub-Saharan Africa and parts of Southeast Asia.
This delay was due in part to the initial high cost of the vaccine but also to difficulty in persuading health officials and communities to accept vaccination of a child for a potential benefit that would not become apparent for 30 or 40 years. Pneumonia and diarrhoea still account for a high proportion of deaths and severe disease in children in the developing world figure 4 [ 24 ].
The most frequent cause of severe pneumonia in children is Streptococcus pneumoniae the pneumococcus , followed by Hib, while rotavirus is the most frequent cause of severe diarrhoea. Thus, the development of effective vaccines against the pneumococcus and rotavirus [ 25 , 26 ] and their incorporation into the EPI programmes of countries with a high child mortality should result in a further major reduction in childhood deaths. Whether pneumococcal conjugate and rotavirus vaccines in developing countries will have the dramatic effect on non-vaccinated subjects observed in industrialized countries, through the induction of herd immunity, remains to be seen.
Incorporation of these vaccines in the routine immunization programmes of the developing world countries, where they could have their greatest impact, has faced a number of challenges. Firstly, these vaccines are more difficult to make than the first generation of paediatric vaccine pneumococcal conjugate vaccines contain 10 or 13 different components and they are consequently more expensive to produce. Secondly, much less was known by the target populations about the infections that these vaccines prevent than had been the case for measles or poliomyelitis.
Introduction of pneumococcal conjugate vaccines has also benefitted from another novel funding process, the Advanced Market Commitment, which has attracted substantial funds from a number of major donors. Infectious and potentially preventable causes of child mortality in [ 24 ].
To assist potential recipient countries in an appreciation of the value to their communities of introducing these new vaccines, GAVI established three special interest groups, the pneumococcal and rotavirus Accelerated Development and Introduction Plans ADIPs and the Hib Initiative.
These groups, based in academic institutions but working closely with Ministries of Health and Finance, non-governmental agencies and the pharmaceutical industry, helped to generate local information on the burden of disease by providing education to all sectors of the community on the importance of the infection in question and, in some cases, undertaking detailed epidemiological studies and even vaccine trials [ 27 ].
They also assisted in negotiations with the pharmaceutical industry over pricing arrangements. As a result of the activities of these groups and others, Hib and pneumococcal conjugate vaccines have been introduced more rapidly into countries with a high child mortality than was the case for hepatitis B vaccine figure 5.
Currently, 30 and 15 of the 56 GAVI eligible countries have introduced pneumococcal conjugate and rotavirus vaccines, respectively www. Finding ways of supporting routine immunization in these countries as they become lower middle-income countries will be a challenge—use of a tiered pricing system and mass purchasing are two of the options that are being explored. The vaccination schedule currently used in the majority of developing countries was developed, largely empirically, when there was only a limited number of vaccines in the routine immunization schedule and when it was considered that vaccines should all be given in the first year of life when clinic attendance is highest.
However, as more and more vaccines are added to the immunization schedule, this approach has had to be reviewed because of the potential for immunological interference between vaccines when given together and because the immunization schedule developed for the original EPI vaccine may not be the one that will give the best immune response for a number of the recently developed vaccines.
Thus, it is likely that more frequent attendances at a vaccination clinic will be needed and that vaccination of children will need to extend into the second year of life, as is already the case in many industrialized countries. Vaccination programmes in the developing world focused initially on prevention of potentially lethal infections in young children because of the high burden of mortality in this age group.
However, there is increasing recognition that the public health benefits provided by vaccination are not restricted to the first year of life but are much broader, for example the prevention of cancer in adults through the immunization of older children with HPV vaccine [ 28 ] and immunization of older children and young adults against meningococcal disease in the African meningitis belt through mass campaigns [ 29 ]. Developing the next generation of vaccines will be increasingly challenging as many of the organisms at which they are targeted have complex structures and life cycles, for example the malaria parasite, or are very effective at outwitting the human immune response through antigenic diversity, such as HIV and influenza viruses.
Development of new vaccines against other important infectious disease targets such as dengue or novel corona viruses should be easier using established technologies but the modest efficacy of a recently tested dengue vaccine [ 30 ] emphasizes that challenges remain even in the development of more conventional vaccines.
However, many novel approaches to the development of new vaccines are being explored [ 35 — 37 ], for example use of attenuated whole organisms as described earlier , reverse vaccinology, which identifies potential candidate antigens through interrogation of the genome, and detailed structural studies, which are helping to define the antigenic determinants that might be able to induce an immune response that would be effective across strains of highly variable organisms such as influenza and HIV viruses.
Additional approaches that are being explored are production of novel particles, and the use of RNA instead of DNA to induce an immune response. New adjuvants directed at improving the immune response are being tried and the success of the RTS,S vaccine [ 31 , 32 ] is due in large part to the use of the powerful adjuvant AS Better methods of preserving vaccines at ambient temperature are being developed [ 38 ] and alternative delivery systems including needle-less devices are being explored [ 39 ], both of which could facilitate uptake of vaccines in hard to reach areas.
Table 3 indicates some of the organisms that are currently the target of vaccine research; recent and continuing technical advances should make it technically possible to develop effective vaccines against most of these pathogens.
However, whether all these vaccines will prove cost effective or be used widely enough to provide a sufficient financial return to the manufacturer is uncertain, as illustrated by the recent case of a serogroup B meningococcal vaccine developed using an innovative technical approach but whose deployment in the UK is being queried on the grounds of cost effectiveness [ 40 ].
Some of the infectious diseases currently the target of research to develop new or improved vaccines. It has, until recently, been the usual practice to have a standard national vaccination policy implemented country-wide. However, as vaccination programmes include an increasing number of vaccines and more complex schedules, targeted vaccination programmes based on a sound local knowledge may become an important way of improving efficiency and reducing costs.
For example, in Nigeria, with its large population, the new serogroup A meningococcal conjugate is being deployed only in the states that are known to be at risk of epidemics. Developing a new vaccine to the high standards required is expensive and new vaccines are bound to be costly until these recovery costs have been paid off. However, once research and development costs have been recouped through the sale of the vaccine at an appropriate price in industrialized countries and sale volume has been increased through adoption of the vaccine in developing countries with their large populations, experience has shown that the costs of a vaccine fall, a fall sometimes aided by vaccine manufacture in a developing country.
It is probable that effective vaccines will be developed against the major infections such as HIV, TB and malaria, although it is difficult to predict how long this will take, and that eventually these infections will cease to be a major public health priority even if they cannot be eradicated completely. Ensuring the maximum benefit that vaccination can provide against infectious diseases will be achieved only if there is global, high-level surveillance to detect the emergence of new potentially dangerous infections and also to detect the emergence of strains resistant to the vaccines in routine use as quickly as possible so that countermeasures can be put into place.
As the incidence of infectious diseases declines and living standards improve across the developing world, many developing countries are entering a transition phase in which they have a residual challenge from infectious diseases, such as HIV and tuberculosis, while at the same time experiencing major challenges from emerging non-infectious diseases such as diabetes, cardiovascular disease and cancer. Could vaccination have a role to play in ameliorating this increasing global burden of non-infectious diseases?
Prevention of a substantial proportion of liver and cervical cancers should be achievable by ensuring universal hepatitis B and HPV vaccination, and prevention of some stomach and nasopharyngeal cancers might be possible in communities where there is a high risk of these cancers by vaccination against Helicobacter pylori and Epstein Barr virus infections, respectively. Vaccination to prolong survival from other cancers, as recently demonstrated for prostate cancer, may become practicable, but highly personalized cancer immunotherapy is likely to be too expensive for universal use in even middle-income countries [ 41 ].
Management of chronic conditions such as diabetes and hypertension is difficult in communities with limited access to healthcare and it is possible that vaccination against these conditions could help by reducing the need for frequent contacts with the health system, although there is much work to be done before this approach could become a practical reality.
Some progress is being made in developing vaccines which modulate the course of diabetes and hypertension [ 42 ]. Vaccination against addiction, including smoking, is also feasible, although very high antibody concentrations are required to achieve an effect [ 43 ], and there are early results suggesting that vaccination against Alzheimer's disease might slow the progress of this condition [ 44 ]. In the coming decades, vaccination is likely to expand its scope beyond prevention of the common infections of childhood which has been its main success so far.
Vaccination has achieved much since the original work of Jenner years ago, and many new vaccines are likely to be developed within the next decade, including some directed at non-infectious diseases. For that reason, people who are vaccinated must take precautions when caring for the place on their arm where they were vaccinated, so they can prevent the vaccinia virus from spreading.
For most people with healthy immune systems, live virus vaccines are effective and safe. Sometimes a person getting a live virus vaccine experiences mild symptoms such as rash, fever, and head and body aches. In certain groups of people, complications from the vaccinia virus can be severe.
The Smallpox Vaccine Safety page has more information about who is more likely to experience these side effects. Smallpox vaccination can protect you from smallpox for about 3 to 5 years. After that time, its ability to protect you decreases. They also tested antibody response to a specific viral protein. In previously immunized individuals they detected an antibody response prior to booster immunization as well as a strong response four weeks after booster immunization.
In newly vaccinated individuals, however, the antibody response to the specific viral protein was virtually undetectable. And because smallpox has an incubation period of from 12—14 days, this provides a window of opportunity for memory B and T cells to expand and attack the infection before the onset of clinical disease.
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