In the first half of the 20th century, summers in the U.S. were punctuated by sporadic outbreaks of paralytic poliomyelitis in school-age children. In the 1940s, more than 30,000 children were disabled by polio every year (asamonitor.pub/3CCVsYS). Parents were afraid to let their children play outdoors during “polio season.” This dire state of affairs ended with the development of the injectable inactivated vaccine by Jonas Salk in the 1950s and the subsequent development of the oral live attenuated vaccine by Albert Sabin (asamonitor.pub/3CCVsYS). As humans are the only reservoir for poliovirus, the live attenuated vaccine and resulting population immunity completely eliminated polio from the U.S., except for the rare cases brought in by foreign travelers (asamonitor.pub/3sb8bwO). Polio has been nearly eliminated worldwide, with just six cases reported in 2021 (asamonitor.pub/3z8HVHF).
A recent case of paralytic poliomyelitis in New York state in an unvaccinated individual has garnered national attention, highlighting the continued importance of this polio vaccination in children (asamonitor.pub/3sb8bwO). It is notable that infection was not the wild-type poliovirus. According to the CDC, “the last case of wild poliovirus acquired in the United States was in 1979” (asamonitor.pub/3T8tNps). Since 1994, the Western Hemisphere has been “free of indigenous wild poliovirus.”
That being the case, what caused paralytic poliomyelitis in New York? The virus isolated from the patient in New York was genetically confirmed by the New York State Department of Health and the CDC to be a “vaccine-derived poliovirus” from a Sabin-type oral polio vaccine (asamonitor.pub/3sb8bwO). Unfortunately, the live attenuated polio vaccine can occassionally undergo a mutation that restores its ability to cause paralysis.
Polio and the poliovirus
The causative agent of polio, poliovirus, was first isolated in 1909 through the efforts of Erwin Popper and Karl Landsteiner (J Virol 1999;73:4533-35). Taxonomically, the “single-stranded positive-sense RNA” poliovirus is in the family Picornaviridae and the genus Enterovirus. There are three different serotypes of poliovirus, aptly named type 1, type 2, and type 3, each with varying capsid protein coatings.
Polio was initially thought to be a respiratory virus spread through coughing. Infection can occur via exposure to “droplets from a sneeze or cough of an infected person” (asamonitor.pub/3S5hjOk). However, in 1939 Albert Sabin demonstrated that the primary route of spread was through ingestion of infected fecal matter and that the primary site of viral replication was the GI tract (Emerg Infect Dis 2022;28:743-6).
Most patients infected with the poliovirus are completely asymptomatic. About 25% of patients exhibit “flu-like symptoms,” which may include fatigue, fever, headache, nausea, and stomach pain. Depending on the poliovirus type, only one in 200-2,000 infections results in a case of paralytic polio.
Cellular entry of the poliovirus is mediated by CD155, which is also known as the poliovirus receptor. CD155 is also the entry receptor for alphaherpesviruses, as well as a recognition molecule for natural killer cells (Virology 2006;344:9-16). CD155 is widely distributed in tissues, particularly lymphoid tissues. It is not known why the virus enters neurons in 1%-2% of cases. However, upon entry into neurons the virus is transmitted to the spinal cord, where it replicates in motor neurons and produces muscle paralysis.
Vaccine types – inactivated virus and live attenuated virus
Initial vaccine efforts against the poliovirus in the U.S. occurred in the 1930s, primarily by teams led by Maurice Brodie and John Kolmer. Brodie and his colleagues at New York City’s public health laboratories attempted to develop an inactivated vaccine (Am J Public Health Nations Health 1936; 26:119-25), while Kolmer and his colleagues from the Institute of Cutaneous Medicine in Philadelphia attempted to develop a live attenuated vaccine (Med Hist 2006;50:253-4). Both efforts failed. The inactivated virus vaccine did not induce sufficient levels of antibodies. The live vaccine was insufficiently attenuated and could cause paralytic polio.
The high rates of polio in the first half of the 1950s gave new urgency to vaccine development efforts. Jonas Salk and his colleagues at the University of Pittsburgh developed a vaccine by inactivating the virus with chemicals such as formalin. Field trials conducted in 1954 demonstrated efficacy against all three poliovirus serotypes and 90% efficacy for preventing paralytic polio (asamonitor.pub/3CCVsYS).
While Salk was developing his vaccine, Albert Sabin and Hilary Koprowski were developing an orally administered live attenuated virus vaccine. To attenuate the virus, Sabin repeatedly passed the virus through primates to obtain a virus that did not efficiently reproduce in human cells (J Biol Chem 2018;293:15471-82). The hope was that the resulting virus was close enough to the human form to induce potent antibodies, while not sufficiently potent to cause paralysis. Recent research has shown that Sabin’s attenuated virus was particularly poor at reproducing in neural tissue, accounting for its lack of neurotoxicity while still promoting an effective antibody response (J Biol Chem 2018;293:15471-82). Unfortunately for Sabin, the success of the Salk vaccine made his research appear unnecessary. Sabin and his colleagues struggled to find financial support for their research. As a result, many of the initial trials for the Sabin oral polio vaccine were conducted in the former Soviet Union.
The Sabin vaccine is much cheaper to produce and does a better job at mimicking the way in which polioviruses infect an individual (oral entry into the oropharynx and gastrointestinal system). As a result, it provides mucosal immunity, complementary to the systemic immunity provided by the injected inactivated virus vaccine. The Sabin vaccine also provides substantially longer-lasting immunity than the Salk vaccine. Finally, because the vaccine is a live attenuated virus, population immunity can be achieved without 100% inoculation. The near eradication of poliovirus is a result of the widespread use of the Sabin vaccine.
Two-tiered immune defense
When a poliovirus infection occurs or when a person is orally dosed with an attenuated polio virus vaccine, in response, the immune system mounts a mucosal immunoglobulin (Ig) A mediated response (Annu Rev Microbiol 2005;59:587-635). This prevents the replication of the poliovirus within the gastrointestinal system. In contrast, the immunity afforded by injection with the inactivated poliovirus vaccine is mediated IgG and IgM, which prevents viral infection of CNS-based motor neurons.
In that regard, one can think of there being internal and external layers of defense for poliovirus infection. The protection provided by the injected inactivated virus vaccine prevents systemic infection; however, it does not prevent mucosal replication, and thus can allow the silent (i.e., asymptomatic) spread of poliovirus to others.
If this is the case, one might think that it makes the most sense to utilize the vaccine that prevents the spread of the disease to other individuals, right? Well, the answer is not so simple. Since 2000, the polio vaccine used in the U.S. exclusively is the inactivated virus vaccine. This decision was made because of well-documented cases of paralytic polio resulting from viral shedding of individuals receiving the oral poliovirus vaccine (termed vaccine-associated paralytic polio) (asamonitor.pub/3T8tNps).
Live attenuated vaccine reversion and vaccine-derived polioviruses
In these cases of vaccine-associated paralytic polio, poliovirus neurovirulence may result from the loss of attenuating mutations, mutations which compensate for the attenuating mutations, or from recombination with a virulent virus (Evolution (NY) 2011;4:635-43; MMWR Morb Mortal Wkly Rep 2022;71:786-90). RNA viruses like the poliovirus and the live attenuated polio vaccine virus have higher mutation rates than DNA viruses. Between 1980-1999, there were a total of 162 cases of paralytic polio within the U.S. Of these, 154, or 95%, were vaccine-associated paralytic polio (asamonitor.pub/3T8tNps).
Current case in New York
This brings us to the current case in New York State. In the July 2022 case from Rockland County, New York, genetic tests performed at the New York State Department of Health and confirmed by the CDC showed that the vaccine-associated paralytic polio case was caused by a Sabin type 2 poliovirus. Therefore, the CDC concluded that the virus came from outside the U.S., where oral poliovirus vaccines are still used. Monitoring for additional polio transmission was done through the genetic testing of sewage samples (asamonitor.pub/3TrZKcd). These analyses produced 69 “positive samples of concern.” Of these samples, 62 were genetically related to the case in Rockland County. The remaining seven positive samples were obtained from Orange County (one in April 2022) and New York City (two in June and four in July 2022). The lineages obtained showed that the viruses were also “vaccine-derived poliovirus… or variants of the revertant polio Sabin type 2 poliovirus.”
Current vaccines and schedule
As previously noted, in the U.S., only inactivated poliovirus vaccines are utilized. However, in other parts of the world, the oral poliovirus vaccine remains utilized for the same reasons they were adopted in the 1960s in the U.S. – they afford better immunity, the immunity lasts longer, they’re easier to give, and they’re much less expensive.
According to the most recent CDC guidelines, children should receive their first polio vaccination at 2 months, with additional doses at 4 months, 6-18 months, and at 4-6 years. The timings of these vaccinations are especially important at younger ages, as decreasing the time between doses or dosing at younger ages tends to result in lower seroconversions.
With the eradication of type 2 poliovirus in 2015, countries using the oral polio vaccine synchronously switched from the trivalent vaccine (against all three types) to the bivalent one (against types 1 and 3 polioviruses). However, the emergence of vaccine-derived polioviruses, 90% of which are type 2-polioviruses, necessitated the creation of a novel type 2 oral polio vaccine (MMWR Morb Mortal Wkly Rep 2022;71:786-90). Because of the ongoing need to address circulating type 2 vaccine-derived polioviruses and the positive clinical data for the novel type 2 oral polio vaccine, in November 2020 the World Health Organization authorized the Emergency Use Listing of this vaccine, with initial distribution occurring in March 2021 (Vaccine 2022;S0264-410X:00195-5). Between March-October 2021, roughly 111 million doses of this novel type 2 oral polio vaccine were delivered. Genomic monitoring of stool samples were performed in order to track any potential neurovirulent vaccine-derived viruses (MMWR Morb Mortal Wkly Rep 2022;71:786-90). These genomic analyses “of confirmed novel type 2 oral poliovirus vaccine isolates over the period of initial use under Emergency Use Listing authorization affirmed the genetic stability profile of novel type 2 oral poliovirus vaccine, with the World Health Organization approving wider use under Emergency Use Listing.”
“The near-eradication of polio represents a triumph of science and public health. Since there is no nonhuman reservoir of poliovirus, in the next few years polio may join as smallpox, last seen in 1980, as highly infectious, potentially lethal pathogens eradicated through the combination of vaccine science and public health.”
One attempt to obtain combined immunity was the use of sublingual delivery of inactivated poliovirus in combination with a thermoresponsive gel (Hum Vaccin Immunother 2014;10:3611-21). These authors noted in their preclinical mouse-based studies, “the combination of serum and mucosal IgA responses were observed only in animals immunized by the sublingual route using the thermoresponsive gel delivery system – not in those immunized by the intramuscular route, nor in those immunized by the sublingual route with only gel or adjuvant – suggesting that both components are essential for eliciting a response when vaccinating at mucosal surfaces” (asamonitor.pub/3ENh5Zg).
The Global Polio Eradication Initiative was launched in 1988 (asamonitor.pub/3ENh5Zg). The initiative listed four pillars that are crucial for poliovirus. First and foremost is routine immunization, which can be with oral, injected, or a combination of the two vaccine types, depending upon the state of endemic polio within the region. Second, supplementary immunization is warranted for all children less than 5 years old. The third and fourth pillars are surveillance for cases of paralytic polio and “mop-up campaigns” to address focused areas of polio transmission once they have been identified.
The near-eradication of polio represents a triumph of science and public health. Since there is no nonhuman reservoir of poliovirus, in the next few years polio may join as smallpox, last seen in 1980, as highly infectious, potentially lethal pathogens eradicated through the combination of vaccine science and public health.
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