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Vaccination is performed to reduce the risk of infection. Vaccines work with the bodys natural defenses and the result is the development of active immunity against the disease due to the administration of a modified (inactivated or weakened) antigen. Diseases that vaccines prevent can cause severe illness and also death in some instances [1,3,4].
Even with advances in health care today, these diseases can still be very severe. Vaccination currently remains the best means for preventing and controlling the spread of infectious viruses .
General rule: "The more similar a vaccine is to the disease-causing form of the organism, the better the immune response to the vaccine." 
The immunologic memory acquired through vaccination is similar to that acquired after natural infection, but with no risk of the disease .
Many approaches are used to design vaccines. Knowledge about the mechanisms of viruses or bacteria is necessary so that the vaccine can target these and subsequently prevent infection. These include factors such as how cells are infected and the manner in which the immune system responds to this. Vaccine use also depends on the population and its specific location in the world. This is important because the strain of a virus and the environmental conditions, including temperature and exposure risk, may not be the same in various areas. The vaccine transfer routes may also differ geographically .
Live attenuated vaccines
These vaccines are comprised of a version of the living virus. The wild virus has been weakened or attenuated in a laboratory. This is done by repeated culturing and modification of the virus. The attenuated vaccine organism must replicate and produce immunity to be effective. Live attenuated vaccines are comparable to a natural infection. They elicit a strong immune response. They are very effective and often produce sufficient long-lasting immunity with only one dosage, in addition to local and systemic immunity [1,3,4,6].
Live attenuated vaccines most often do not cause infection in an immune-competent person. These are contra-indicated in the immunocompromised patient and pregnant women. Examples of immunocompromised patients include patients who undergo chemotherapy, those infected with HIV/AIDS and or on long term steroid therapy. Severe reactions and interference from circulating antibodies may also occur depending on individual susceptibility [1,3,5].
Live vaccines have the potential to revert back to the virulent strain and cause disease. This has been observed with the live oral polio vaccine. Another disadvantage is that this vaccine has poor stability. It is delicate or fragile and may be damaged or destroyed by light and heat. These need to be stored and handled carefully. The maintenance of the vaccine "cold chain" is vital. The cold chain consists of proper refrigeration from the manufacturer to the beneficiary. It can be exceedingly challenging in low-resource environments. Live vaccines can be contaminated [2,4,7,8].
Examples of live attenuated viral vaccines include the mumps, measles and rubella vaccine (MMR), varicella, zoster, yellow fever, rotavirus and influenza vaccines [1,2].
Inactivated vaccines are composed of whole viruses or bacteria, or fractions of viruses or bacteria and are produced by inactivating or killing of the virus . They are unable to replicate under any circumstances . Inactivated vaccines respond to the immune system in different ways when compared to live attenuated vaccines. There is less interference from circulating antibodies when compared to live vaccines . The immune response to an inactivated vaccine is humoral and does not elicit cell-mediated immune responses. This can be held in contrast to a live vaccine, in which the immune response can be likened to that involved in a natural infection [1,2,3].
Inactivated or killed vaccines are stable and the constituents are clearly defined. They are unable to cause illness from an infection and can therefore be used in immunocompromised patients [2,4]. However, inactivated vaccines are not as efficient as live vaccines and require 3-5 doses to maintain protective immunity. The antibody titer may also decrease with time, which indicates waning immunity. Adjuvants are required to "boost" the antibody titers to prevent this [3,4].
Examples of whole cell inactivated vaccines:
Currently available whole-cell inactivated vaccines for viruses are polio, Hepatitis A, influenza and rabies vaccines [2,3].
Fractional vaccines include subunits (influenza, hepatitis B, human papillomavirus, acellular pertussis, anthrax) and toxoids (tetanus, diphtheria) [2,3].
This type of vaccine includes parts of the virus or bacteria and contain essential antigens and not all the molecules of the virus. Therefore, side effects are less common .
Toxoid vaccines prevent diseases caused by bacteria that produce toxins. The toxins are weakened so that they cannot cause illness, producing toxoids. When the immune system receives a toxoid vaccine, it fights the natural toxin off. The DTaP vaccine includes bacterial tetanus and diphtheria toxoids .
Pure polysaccharide-based vaccines:
Pure polysaccharide vaccines are currently used for three diseases: meningococcal disease, pneumococcal disease, and Salmonella typhi. The immune response is T-cell independent. These vaccines can stimulate B cells without the help of T-helper cells. T-cell-independent antigens are not immunogenic in children under two years, because their immune systems are immature. Repeated doses of the pure polysaccharide vaccines are unable to induce a booster immune response. Immunoglobulin M (IgM) predominates and small amount of Immunoglobulin G (IgG) is produced. Induced protein antigens have more functional activity than the antibody formed with polysaccharide vaccine .
Conjugate polysaccharide vaccine
At the end of the 1980s, it was discovered that the problems noted in the pure polysaccharide (T-cell independent) vaccine could be resolved through conjugation. Conjugation is a chemical process where the polysaccharide is combined with a protein molecule. The immune response is changed from T-cell independent to T-cell dependent. This leads to greater antibody booster immune response to several doses of the vaccine and increased immunogenicity in infants .This type of vaccine react to different bacteria. These bacteria contain antigens with an outer coating of polysaccharides. The antigen is disguised by the polysaccharide coating making it difficult for an infant or young child's immature immune system to react and recognize to it. Conjugate vaccines are used for these bacteria because they conjugate the polysaccharides to antigens. The immune system responds well to conjugation, making this a powerful vaccine [1,2]. Haemophilus influenza type B (Hib) vaccine is an example of a bacterial conjugated vaccine .
SA-EPI schedule viral vaccines
The EPI-SA (Expanded Programme on Immunisation in South Africa) was first introduced to our country in 1995, and covered:
pertussis (whooping cough)
Combination vaccines and improved vaccines also contributed to a more successful program. It is important to take into account the fact that schedules for immunisation need to be adapted to the specific disease epidemiology of the individual countries/areas .
The following notable milestones have been reached in the history of EPI-SA:
1995 - Hepatitis B vaccine
1999 - Haemophilus Influenza type B (Hib) vaccine
2000 - BCG route administration changed from percutaneous to intradermal
2002 - Neonatal tetanus eliminated
2006 - SA declared polio-free
2008 - conjugated pneumococcal and rotavirus vaccines
2009 - whole cell pertussis vaccine to acellular pertussis vaccine
OPV (oral polio vaccine) replaced by IPV (inactivated polio), doesn't have the risk of VAPP (vaccine-associated paralytic polio)
Hib booster at 18 months introduced. 
Viral vaccines currently in the EPI schedule of South Africa include the following:
Hepatitis B vaccine
Hepatitis B vaccine
This vaccine is administered at 6, 10 and 14 weeks of age. It is not administered at birth because transmission in neonates is mostly horizontal, not perinatal .
Hepatitis B is mainly a viral infection of the liver. Many people that acquire it are at high risk for serious illness and death from liver cirrhosis and primary liver cancer .
Immunisation of infants is recognized as the best strategy to prevent chronic HBV infection. It first became available in the US in 1982. WHO recommended that the vaccine should be integrated into all national immunisation schedules in 1992 .
These are considered as the priorities for HBV immunization:
routine infant vaccination
prevention of mother to child transmission
catch-up vaccination for older age groups. 
The vaccine is usually administered intramuscularly into the right thigh.
Rotavirus is an icosahedral, non-enveloped virus of the Reoviridae family. Rotavirus is transmitted via the oral-faecal route, but can also be transmitted via the respiratory route. Infections are usually seasonal and include symptoms such as vomiting and watery diarrhoea . This virus is the most common cause of morbidity and mortality from paediatric diarrhoea and dehydration.
Rotavirus infections are often complicated with multiple strains of the virus and even other enteric pathogens, resulting in a more severe infection. 
Vaccines are administered orally at six and fourteen weeks of age and are live, attenuated vaccines. 
In May 2009, the Minister of Health of South Africa introduced the rotavirus vaccine to the EPI schedule of all infants in SA. 
These vaccines are used to prevent polio in people who have not been previously infected by the virus. There are mainly two types of polio vaccines available:
OPV - live-attenuated oral polio vaccine
IPV - inactivated polio vaccine 
OPV is administered orally at birth and at six weeks of age. This vaccination confers lifelong immunity .
IPV is administered at 6, 10 and 14 weeks, and 18 months. This is very effective in immunocompromised patients. Immunisation success is between 92 and 100% .
OPV has almost no side-effects, but in some rare cases patients may experience headaches, diarrhoea or muscle pain. IPV is also very safe, but mild side-effects may include soreness at the site of injection, fatigue and low-grade fever .
Contra-indications for vaccination include the following:
patients with a history of allergic reaction to any previous polio vaccines
patients with an allergy to the antibiotics neomycin, streptomycin or polymyxin 
Measles is generally considered to be a self-limiting disease, but may cause serious complications such as pneumonia, blindness, encephalitis or even death in certain cases .
The vaccine that is given intramuscularly into the left thigh is a live attenuated vaccine, and is given at nine and eighteen months of age respectively .
The most common side-effects experienced include fever and a mild rash. 
Patients who should not be vaccinated include:
people who had an allergic reaction to a previous measles vaccination
severely immune-compromised patients
those receiving chemotherapy, radiation therapy or high-dose corticosteroids
HIV-positive patients 
Viral vaccines that are not currently covered in the EPI schedule of South Africa include Mumps, Rubella, Varicella Zoster and Hepatitis A.
Viral vaccines not included in the SA-EPI schedule
The extra vaccines that are available in South Africa are optional in the private sector. This includes vaccines against the following viruses:
Rubella (German Measles), Measles and Mumps (given in combination as "MMR" vaccine).
Human papilloma virus (HPV) and many others.
Vaccines that are used for specific viral infections caused by Influenza, Rubella, Mumps, Measles, Hepatitis A and Human papilloma virus will be discussed.
Hepatitis A vaccine:
Hepatitis A is a naked RNA virus that comes from the Picornaviridae family. It is transmitted via the faeco-oral route through contaminated food or water, direct person to person contact, blood transfusions and intravenous drug use etc. There is no treatment available and vaccination to prevent the infection is thus of paramount importance, particularly in susceptible persons .
In South Africa, an inactivated HAV vaccine is used e.g. Havix (GlaxoSmithKline), VAQTA (Merck &Co.), Avaxim (Sanofi Pasteur). In China, a live attenuated vaccine is used. The HAV vaccine and immune globulins are utilized in pre- and post-exposure prophylaxis and should be administered to persons aged 2 to 40 years within two weeks of exposure (but preferably within 72 hours). This is only available in the private sector. The vaccine consists of a minute amount of the Hepatitis A virus, which has been chemically altered or inactivated ("killed"). It is injected in the upper arm, usually in two doses, one month apart.
Hepatitis is a very common virus in South Africa and usually occurs in children (between 1 and 4 years old).
The reason for not implementing the Hepatitis A vaccine in the SA-EPI schedule is because it is not currently considered a high health risk priority. It tends to be a mild disease in children, which does not cause permanent liver damage and also does not become chronic. However, in 1% of cases Hepatitis A tend to become very serious and cause severe liver damage and death in children that have been infected .
Hepatitis A is a serious disease in adults and the vaccine is recommended for groups such as health care workers, staff taking care of young children, clients and staff in mentally- handicapped institutions, food industry workers, persons with liver diseases and those traveling to regions with high hepatitis A rates e.g. Africa, Central America, South America, the Caribbean, Mexico, Asia, Southern Europe and Eastern Europe 
Influenza viruses A, B and C come from the family Orthomyxoviridae. This virus is a helical ssRNA virus with an envelope and it is important to note that it consists of a segmented linear genome which can change and undergo antigenic drift or even antigenic shift. The latter can result in an epidemic. Major changes only occur with Influenza type A. It is thus very important to get vaccinated every year at the beginning of autumn .
Transmission: Influenza is rapidly spread via droplets and reinfection is common because of new strains.
Persons at risk of contracting influenza: Children <2 years, adults >65 years and children <18 on chronic aspirin, pregnant woman, people with chronic diseases e.g. diabetes, hepatic disease, pulmonary disease, cardiac disease etc. immunosuppressed people e.g. with HIV and persons with morbid obesity are at great risk .
The influenza vaccine is a trivalent vaccine and is affective against the following strains: H1N1, H3N2 and B. These are updated annually by the WHO (World Health Organisation) influenza network. In South Africa this is an inactivated vaccine and is safe for pregnant women and children 6 months and older.
Contraindications: These include a history of anaphylaxis or severe reaction to the abovementioned vaccine. It is also not indicated for persons who developed Guillain-Barre syndrome within 6 weeks of the vaccination or children less than 6 months old. Persons with egg allergy should also not be vaccinated because of the egg-based technology used to produce the vaccine.
Side effects of the vaccine injection include: Soreness, redness, swelling at injection site as well as fever and aches. It lasts about 1-2 days .
Measles, Mumps and Rubella vaccine:
The MMR vaccine is a combined shot of three live attenuated viruses against measles, mumps and rubella (German measles). Generally it is administered to children around the age of one year and again at the age of 5 or 6 years .
Although the Measles vaccine forms part of the SA-EPI schedule, Mumps and Rubella do not. All three are viruses are highly contagious and are spread through droplet or airborne transmission .
This vaccine is not to be given to persons with severe immune deficiency or active tuberculosis. HIV positive asymptomatic persons may be vaccinated.
Rubella poses a major risk in pregnancy. Congenital rubella resulting in serious may be contracted by the mother during pregnancy .
Side effects caused by the MMR vaccine: Adverse reactions are rare, but possible. Fever, malaise and a rash 5 to 21 days after the first shot, in addition to joint pain (especially in the older population) are examples. Anaphylaxis may also occur due to egg allergy. There is no relation between the MMR vaccine and autism.
Passive immunization entails the administration of normal immunoglobulins to non-immune individuals as post-exposure prophylaxis .
Human papilloma virus (HPV) vaccine:
The Human papilloma virus is a naked dsDNA virus from the Papillomaviridae. High risk HPV types that can lead to cancer include Type 16, 18, 31 and 52. Low risk HPV types causing warts or condylomas are Type 6 and 11 .
The vaccines available in South Africa's private sector: Gradasil (Merck) which is against HPV type 6, 11, 16 and 18. Cervarix (GSK) against HPV 16 and 18 .
This vaccine prevents infection and the risk of developing complications such as cervical cancer, genital warts and other cancer, therefore it is recommended for women between the age of 9 and 25 years old who have not been exposed to the virus .
The HPV vaccine is based on a virus-like particle which is assembled form recombinant coat proteins. The L1 capsid protein self-assembles into particles which mimic the natural HPV. This is a very safe vaccine, as it contains no toxic or infectious particle and is designed to elicit virus-neutralizing antibody responses to prevent infection. Waning of immunity occurs after 4-5 years after the vaccination has been administered .
Contraindications and precautions: Persons with hypersensitivity to yeast should not receive the vaccine as this is used in its production.
New and novel approaches to viral vaccines
New approaches to the development of vaccinations are progressively becoming more centered on genetic engineering as opposed to live, killed or purified vaccines . This is due to the fact that the complete genomes of more pathogens are being reported. There is also a better knowledge of molecular pathogenesis and immunity, in addition to genomics and proteomics. Scientists are now able to synthesise an immunogenic protein without having to grow the organism to do so .
The biggest challenge at present is to apply this fundamental knowledge to create vaccines that initiate a more protective immune response than the natural infection would. These vaccines should also be more effective against chronic viral diseases and subsequent cancer in some cases .
In the last 5 - 10 years, some vaccines that are designed based on increased knowledge of the human immune system have progressed to clinical trials . Many of these strategies are based on improved ways of inducing antibody production, or inducing production of cytotoxic T lymphocytes (CTLs) that are able to detect and destroy virus-infected cells. The latter can detect any kind of viral protein produced by the infected host cell, even if it is not on the surface of the cell. In the case of HIV and HCV infections, CD4+ T cell responses have been found to be essential in the maintenance of CD8+ T cell function and control of viremia. In HIV, the elimination of CD4+ T cells limits the ability of vaccines to induce T-cell help during early infection. Memory CD8+ T lymphocytes are unable to transition into central memory CD8+ T-cells as a result of chronic antigen stimulation during a persistent infection. CD8+ cells proliferate more efficiently when re-exposed to the antigen, but because chronic viral infections prevent this highly effective form of T-cell memory, the disease is able to persist. Thus, the challenges for an effective viral vaccine are to induce long-lasting central memory CD8+ T cells as well as CD4+ helper T lymphocytes. A lot of research on novel approaches to vaccine development has been focused on HIV, HCV and HPV .
Development of vaccines in the past decade has led to new approaches towards the prevention of viral infections. These are primarily focused on cell-mediated immunity and on the production of neutralizing antibodies which act against specific pathogens and protect against infection . The emphasis is also on comprising defined epitopes and on the synthesis of peptides that correspond with microbial protein sequences . An example of elicit epitope formation is genetic engineering of synthetic recombinant vaccines e.g. influenza. When this vaccine was made, oligonucleotides coding for certain T- and B-cells were inserted into the flagellum of the Salmonella vaccine strain . When a mixture of these cells was used in the vaccine, it was found to be effective against several strains of influenza. This vaccine also retained its effectiveness for a minimum of 7 months. These results have shown that these types of vaccines may potentially serve as a long-range and broad-spectrum preventative therapy, particularly against influenza. Using this technology as a platform, HIV vaccinations based on similar mechanisms may be developed.
"Platform technology" is another new approach to viral vaccination . A new form of pox virus vectors have been developed which have the ability to express immune-modulating proteins, co-stimulatory molecules and many antigens simultaneously. Therion Biologics developed this technology and have certified that it is safe for human use, well-tolerated by recipients and does not difficult to manufacture .
AlphaVax recently developed a safe vaccine against alphaviruses e.g. alphavirus causing Venezuelan Equine Encephalitis or Chikungunya. They developed a specific system that can produce what they call "replicon partials", which makes the vaccine safe for human use. It is also responsible for the formation of a platform for vaccines for other diseases that are caused by organisms that possess heterologous antigens like Marburg, Lassa fever, Influenza and Ebola .
Acambis ChimeriVax technology was used in the production of the 17D vaccine strain of the Yellow Fever virus. It was used to produce a "chimeric live virus" which would comprise a capsule with enveloped prME genes of west Nile virus and the genes that have no structure in this pathogen .
These types of approaches have been used before in Dengue virus vaccine trials and in Yellow fever/Japanese encephalitis vaccine trials. After peripheral inoculation of the prME wild-type protein from west Nile virus and Yellow fever chimera, young and immunocompetent mice that were tested did not develop encephalitis . However, this was contradicted in the parent WN NY99 strain. The neurovirulence of Yellow fever or West Nile wild-type chimera was reduced dramatically and showed point mutations in specific sites of the E protein. These vaccines are currently in the clinical trial stages.
In animals such as hamsters, monkeys, horses and mice, the vaccine has proven to be effective and protective. When single dose of vaccine was given to Rhesus monkeys (vaccination containing triple FVR single F, double VR), mutations caused viraemias that were the similar YF-VAXÂ® viraemias in duration, but much less harmful in all other aspects . The safety profile of the vaccine construct supported lower viscerotropism. After challenge, the ChimeriVax-WN-vaccinated Rhesus monkeys showed no clinical signs and quick seroconversion followed . In conclusion, ChimeriVax-WN is a promising, safe, single dose, protective, live attenuated vaccine that will potentially provide protection against the West Nile virus in the future.
South Africa has the greatest number of HIV-infected individuals in the world . This necessitates the rapid development of a new HIV vaccine to reduce the high morbidity and mortality rates of the population and therefore transmission rates. However, the Human Immunodeficiency virus poses one of the greatest challenges in the creation of a possible viral vaccine, as this retrovirus has a marked ability to mutate. Also, movement of the virus between fused cells and syncytia protects it from neutralisation by antibodies in an infected individual .
There is a great variation in HIV sequences in each infected person at any one time, whereas there is usually only one predominant strain of the influenza virus that affects a population (country) annually . If new influenza vaccines are needed yearly, HIV vaccines would need to be updated and remodelled far more frequently if based on current methodology. In addition, animal models that are useful for research are not perfect and protection has not been translated to human clinical testing . The current aim is to identify conserved epitopes of the viral surface glycopeptides that may serve as possible antigenic targets .
There is a limited understanding of efficient ways to induce protection against the HI virus in humans. Up until now, vaccine designs have been focused on the production of either good antibody or good T-cell responses. It is likely that that a good HIV vaccine will have to prompt both of the abovementioned immune responses . Recent HIV vaccine candidates have only reached phase 3 clinical trials . These included the HIV-1 subtype B envelope protein vaccine and an adenovirus vector vaccine which expresses HIV-1 subtype B Gag, Pol and Nef proteins. These gave no protection. The third Thailand RV144 vaccine provided 60% protection for a year, but this protection rapidly decreased over the next few years . The partial success in the latter case has provided a basis for further research with regard to new approaches, as it was based on antibody response, but not neutralizing antibodies . Also, new data that has emerged from the failed STEP trial which supports the notion that the combination of a vaccine that induces cellular immunity with immunogens that induce protective antibody responses, may be the best approach to HIV vaccination .
More recently, two HIV vaccine candidates, the SAAVI DNA-C2 and SAAVI MVA-C vaccines, have reached phase 1 clinical trials. South Africa and the USA have been funded with regard to this project . The SAAVI DNA-C2 vaccine is based on a mixture of two DNA plasmids. The first consists of reverse transcriptase, Tat and Nef as well as HIV-1 subtype C Gag. The second plasmid consists of an HIV-1 subtype C truncated envelope protein . The second vaccine is based on the modified vaccinia Ankara (MVA) and is comprised of HIV genes that match the SAAVI DNA-C2 vaccine . In the first phase placebo-controlled trial, it was found that these vaccines are safe are well-tolerated and also induce significant CD4+ and CD8+ immune responses. At the end of 2011, a study extension was approved . This trial is currently on-going and provides further understanding of new mechanisms or approaches for any possible future HIV vaccine candidates, should these trials fail. Cell-mediated immunity in combination with antibody responses is certainly a novel approach to future possible HIV vaccination.
Herpes simplex virus (HSV) vaccines
For the last few decades, scientists have attempted to create vaccines that are effective against genital herpes. Previous strategies included whole inactivated virion preparations, genetically attenuated live viruses, recombinant subunit vaccines, and gene-delivery vehicles expressing HSV antigens . Most of these attempts failed. However, a glycoprotein D vaccine used in combination with two adjuvants has been proven to be moderately effective in preventing primary HSV-2 genital infection in seronegative women . This is still undergoing clinical trials .
Other novel vaccine strategies include delivery of immunogens using lentiviral vectors. This has been effective in vaccinating against cancer and certain infectious diseases . Advantages of this strategy include low or non-existing population immunity, transgene activity and transduction and lengthened expression of transgenes. Such vectors have been derived from the HI virus and are highly efficient, but potential remaining pathogenicity poses too high a risk for clinical use .
The feline immunodeficiency virus has been considered as a reasonable alternative, as this lentovirus in domestic cats is similar to HIV-1, but cannot infect humans . Trials have proved that these vectors are safe for use in vivo and in vitro in humans. A candidate vaccine, designated vLAW-gB1/VSV or LAW34, has been developed, but needs much improvement before it can be tested on humans in clinical trials . A protective vaccine is still many years away and LAW34 could be administered alone or combined with other delivery systems in the future .
Cytomegalovirus (CMV) vaccines
A recombinant CMV envelope glycoprotein B vaccine has recently been developed. However, it has only induced a protective immune response in approximately 50% of pregnant women . In the future, an improved model may be used to reduce maternal and congenital infection . The basic strategy involves the induction of virus-neutralizing antibodies or phosphoprotein 65 to activate cell-mediated immunity in the host .
There has also been some success with a glycoprotein B-subunit trial vaccine in solid-organ transplant recipients. This was attributed to the generation of protective glycoprotein B-antibody titres . However, this specific type was not effective in generating a protective response in maternal or congenital infections and was even less successful in protecting immunocompromised patients than the former vaccine in protecting pregnant women. The necessary immunosuppressive therapies in organ transplant patients reduce pre-existing immune responses, which is the most probable reason for decreased vaccine efficiency .
The high rates of CMV disease in vaccine and placebo groups suggest that a vaccine alone will not be sufficient in the immunocompromised . If an effective CMV vaccine is developed, pre-emptive therapy for solid-organ transplant patients may be preferred above antiviral prophylaxis in most cases . Recently completed clinical trials suggest that this novel approach to CMV vaccination may be effective in the future.
As seen in the evidence discussed above, a more comprehensive understanding of viruses, the human immune system and vaccination has been gained over the last few decades. Although there is still much to be discovered, recent studies and clinical trials reveal that new and novel approaches to viral vaccination may prove successful in the future for prevention of currently incurable diseases such as HIV or HSV.