Virology tidbits

Virology tidbits

Tuesday, 11 March 2014

Poliovirus - a model for a (nearly) successful vaccination campaign

Poliomyelitis or infantile paralysis is a potentially fatal infectious disease of the spinal cord and the brain caused by Poliovirus - a small positive strand RNA virus part simliar to other Enteroviruses such as the Coxsackieviruses, Rhinoviruses and Echoviruses. Serologically three different serotypes can be distinguished, Poliovirus I, II and III, each with slightly different structures of the capsid protein. The three subtypes not only differ in the structure and properties of the capsid protein but also in their pathogenicity, with Type II being the mildest. In children, following an incubation period of about 3-20 days with minor symptoms, a second phase may occur which is characterized by meningitis and paralysis. In adults the first phase is often skipped, presenting themselves with paralysis and meningitis. Both phases are accompanied by high fever and general malaise, including diarrhea as well as vomiting and a severe headache.
Poliomyeltis was a disease very common in the western hemisphere up to the mid-1950s, declining after the introduction of the first successful vaccine, an inactivated vaccine (termed IPV) which protects vaccinated children against all three types of Poliovirus and developed by Jonas Salk at the University of Pittsburgh. Later Alfred Sabin would propagate his vaccine, a live attenuated vaccine (termed OPV for Oral Polio Vaccine) and the Salk vaccine would be replaced over time by this one. Since the 1990s however the use of OPV is discontinued in most countries since it has been shown that OPV can recombine with other Enteroviruses and cause a disease resembling poliomyelitis in non-vaccinated children and in those children which have been vaccinated but where the vaccination failed. Additionally, it also has been shown that a significant number of children which were vaccinated with OPV would shed virus in their faeces - a considerable problem in areas with poor sanitation and thus be able to infect unvaccinated members of the household. Without dwelling too much on the disease, the introduction of a mass vaccination program in the 1950s was a success story, second only to the introduction of the smallpox vaccine. Although only a relative small number of those infected with the virus required hospitalization -if showing any symptoms at all- those who were admitted often faced permanent paralysis of the extremities, the extent depending which part of the spinal cord was infected. Death was often avoided only by placing the children in iron lungs (see image above); even if the children survived often they would face paralysis and motoneuron disease later in life, often 30 to 40 years after the initial infection cleared. This disease however is not induced by the virus itself but due to the death of motoneurons during the initial infection and subsequent "rewiring" of the nervous system.
Poliovirus is transmitted via the faecal-oral route and is able to survive the acidic pH of the gastrointestinal tract. In asymptomatic patients (95% of the infections are asymptomatic), the virus can only be detected within the bloodstream followed by viral clearance. In 5% of the cases however the virus is able to infect and replicate other cells as well, such as the brown fat, mononuclear phagocyte system (which includes microglia) and muscles - causing headaches, menignitis and general malaise. It is only in 1% of these cases that the central nervous system is infected and paralysis to a varying degree occurs, including breathing difficulties. In general, this last phase of the disease (the “neurological phase”) is considered to be accidental.
So why elaborate on a disease which is close to be eradicated, with epidemics belonging to the past? First, the disease is not eradicated yet. Deadlines have been announced only to be replaced with new deadlines. According the WHO, Polio is still endemic in parts of Afghanistan, Nigeria and Pakistan. Vaccination campaigns in these countries are hampered by Muslim fundamentalists which believe that the vaccination of girls in particular is a campaign of the West to “sterilize" them or infecting them with HIV as well as causing apostasy or immoral behaviour. Aid workers are frequently targeted in attacks, fueled by suspicions that they are foreign agents, under the disguise of  providing vaccinations. 
Second, as I pointed out the Sabin vaccine was used for a long time.  Part of the reason of the introduction of the Sabin vaccine was the “Cutter incident” where a batch of the Salk vaccine was shown to cause illness in children following inoculation. This was shown to be caused by inadequate production of the vaccine; the company did not follow the guidelines, government regulators also failed to act and Jonas Salk was eventually cleared. In the early 1960s IPV nevertheless was replaced by the live attenuated vaccine developed by Alfred Sabin. This vaccine has the advantage that -since it is given orallly- it mimics the natural route of infection. Children also might prefer the sweet taste of sugar instead of the pain and scare associated with needles. In an interesting side note, this vaccine was first introduced in the Soviet Union and Czechoslovakia prior to his native US, following a visit of Mikhail Chumakov to the US in 1956. 
However, soon after the introduction of OPV in the US a phenomenon termed “Vaccine Associated Paralytic Polio” (VAPP) was reported, later to be shown to be the result of recombination with other types Enterovirus, especially Coxsackievirus, in the gut of vaccinated children or of mutations of the genome of the vaccine strains. These hybrid viruses (circulating Vaccine Derived Poliovirus or cVDPV) are highly neurovirulent and caused a smoldering outbreak in Egypt and Hispaniola; paradoxically, stringent vaccination with OPV can limit these outbreaks.

So what is to be expected in the future? Hopefully the disease can be extinguished soon, providing that the last remaining pockets vanish. The underlying question is do we need to be vaccinated? The opinions are divided, with the majority opinion be that we need to continue the vaccination for children for a while especially if cVDPV should become a problem.      
To this day, other Non-Poliovirus enteroviruses cause serious disease in humans, such as viral meningitis. A Poliovirus like disease was reported in California between August 2012 and July 2013, with symptoms similar but distinct from Poliomyelitis and not caused by Poliovirus nor cVDPV. 

What can we learn from the mass vaccination program targeting Poliovirus? The Cutter incident lead to the establishment a fund which compensates victims of vaccine failure and the FDA emerged with new powers with similar schemes in other countries. The mass vaccination campaigns highlighted a problem still prevalent in various societies. The so-called Dutch Bible Belt (“Bijbelgordel”) refused vaccinations on religious grounds. An outbreak of Poliomyelitis in 1978 left 110 children paralysed and re-introducing the disease into a community of orthodox Protestants in the US. Despite Church authorities declaring that vaccination is not contradicting Church regulations, continuing refusal by some parents lead to a renewed outbreak in 1992/1993. Regarding Muslim societies refusing the vaccine, it should be noted that vaccine tested and produced in Indonesia under the auspices of Muslim clerics has been approved by the Sharia council in Nigeria, but the damage has been done.
Others reject that Poliovirus is the causative agent of Poliomyelitis altogether; the virus is the product of the disease and despite being infectious in monkeys does not infect humans. Others deny that vaccination prevents this disease; they insists that homeopathic medicine is sufficient. 

In short, resistance against the Polio vaccination is only one example of the resistance met when vaccines are introduced into the public. Replace Polio with Smallpox, Measles or HPV and it is clear that there always people who resist modern medicine.

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