On episode #340 of the science show This Week in Virology, the TWiV teams reviews a MERS-coronavirus serosurvey and an outbreak in South Korea, and constraints on measles virus antigenic variation.
You can find TWiV #340 at www.microbe.tv/twiv.
antigenic variation
Poliovirus escapes antibodies
Antigenic variation is a hallmark of influenza virus that allows the virus to evade host defenses. Consequently influenza vaccines need to be reformulated frequently to keep up with changing viruses. In contrast, antigenic variation is not a hallmark of poliovirus – the same poliovirus vaccines have been used for nearly 60 years to control infections by this virus. An exception is a poliovirus type 1 that caused a 2010 outbreak in the Republic of Congo.
The 2010 outbreak (445 paralytic cases) was unusual because the case fatality ratio of 47% was higher than typically observed (usually less than 10% of patients with confirmed disease die). The first clue that something was different in this outbreak was the finding that sera from some of the fatal cases failed to effectively block (neutralize) infection of cells by the strain of poliovirus isolated during this outbreak (the strain is called PV-RC2010). The same sera effectively neutralized the three Sabin vaccine viruses as well as wild type 1 polioviruses isolated from previous outbreaks. Therefore gaps in vaccination coverage were solely not responsible for this outbreak.
Examination of the nucleotide sequence of the genome of type I polioviruses isolated from 12 fatal cases revealed two amino acid changes within a site on surface of the viral capsid that is bound by neutralizing antibodies (illustration). The sequence of this site, called 2a, was changed from ser-ala-ala-leu to pro-ala-asp-leu. This particular combination of amino acid substitutions has never been seen before in poliovirus. Virus PV-RC2010, which also contains these two amino acid mutations, is completely resistant to neutralization with monoclonal antibodies that recognize antigenic site 2 (monoclonal antibodies recognize a single epitope, as opposed polyclonal antibodies which is a mixture of antibodies that recognize many epitopes. The antibodies in serum are typically polyclonal).
Poliovirus neutralization titers were determined using sera from Gabonese and German individuals who had been immunized with Sabin vaccine. These sera effectively neutralized the type I strain of Sabin poliovirus, as well as type 1 polioviruses isolated from recent outbreaks. However the sera had substantially lower neutralization activity against PV-RC2010. From 15-29% of these individuals would be considered not to be protected from infection with this strain.
Nucleotide sequence analysis of PV-RC2010 reveals that it is related to a poliovirus strain isolated in Angola in 2009, the year before the Republic of Congo outbreak. The Angolan virus had just one of the two amino acid changes in antigenic site 2a found in PV-RC2010.
It is possible that the relative resistance of the polioviruses to antibody neutralization might have been an important contributor to the high virulence observed during the Republic of Congo outbreak. The reduced ability of serum antibodies to neutralize virus would have lead to higher virus in the blood and a greater chance of entering the central nervous system. Another factor could also be that many of the cases of poliomyelitis were in adults, in which the disease is known to be more severe.
An important question is whether poliovirus strains such as PV-RC2010 pose a global threat. Typically the fitness of antigenically variant viruses is not the same as wild type, and therefore such viruses are not likely to spread in well immunized populations. Today some parts of the world have incomplete poliovirus immunization coverage, which together with the reduced circulation of wild type polioviruses leads to reduced population immunity. Such a situation could lead to the evolution of antigenic variants. This situation occurred in Finland in 1984, when an outbreak caused by type 3 poliovirus took place. The responsible strains were antigenic variants that evolved due to use of a sub-optimal poliovirus vaccine in that country.
The poliovirus outbreaks in the Republic of Congo and Finland were stopped by immunization with poliovirus vaccines, which boosted the population immunity. These experiences show that poliovirus antigenic variants such as PV-RC2010 will not cause outbreaks as long as we continue extensive immunization with poliovirus vaccines, coupled with environmental and clinical testing for the presence of such viruses.
Antigenic variation explains recurring acute infections
The rapid clearance of acute viral infections is a consequence of robust host defenses. Survivors of acute infections are usually immune to infection with the same virus. If the immune response is so effective, why do some viral infections – such as the common cold or influenza – occur repeatedly?
Acute infections recur because selection pressure in the host leads to the production of virions that are resistant to clearance by the immune system. For example, when viruses replicate in the presence of antibodies that can block infectivity (neutralizing antibodies), viruses are selected that are resistant to the antibodies. These viruses can then infect individuals who are immune to the original virus. The ability to escape antibody neutralization requires structural plasticity – the ability to tolerate many amino acid changes in virion structural proteins without losing infectivity. Examples of viruses with this attribute are influenza virus and HIV.
While some viruses have remarkable structural plasticity, others tolerate few amino acid changes. We have little understanding of the principles that govern these differences. The limited structural variation of poliovirus (3 serotypes) is in stark contrast to the virions of rhinovirus, which have remarkable structural plasticity (~100 serotypes); yet the two viruses are both members of the Picornaviridae. Whether or not the virion is enveloped is of no consequence: influenza, measles, and yellow fever virions are all enveloped, yet antibody-resistant variants of the latter two viruses are rarely observed.
The practical consequences of structural plasticity are quite clear: they determine whether or not immunization confers sustained protection against infection. The poliovirus, yellow fever, and measles virus vaccines, which have not been changed significantly since they were first developed, induce immunity that lasts a lifetime. In contrast, a new influenza vaccine is needed every year, and no one has yet determined how to formulate a vaccine that protects against all 100 rhinovirus serotypes.
The change of virion proteins in response to antibody selection is called antigenic variation. There are two kinds: antigenic drift, comprising minor amino acid changes such as those which necessitate a new influenza vaccine each year, and antigenic shift. The latter involves acquisition of new structural proteins and a major change in antigenic properties such that the virus is no longer recognized by antibodies in the population. Such ‘shifted’ strains of influenza virus arise periodically when genes encoding structural proteins are acquired from viruses that infect animal hosts. These strains cause worldwide epidemics of influenza that are called pandemics.
Antigenic evolution has been visualized by creating two-dimensional maps in a process called antigenic cartography. These maps are made with data that provide information on the antigenic properties of the pathogen. In the case of influenza virus, the data come from measuring the ability of an antiviral antibody to inhibit hemagglutination – binding of virions to red blood cells. Such maps show how amino acid changes can affect antibody binding to virus particles, which cannot be done by comparing nucleotide sequences of different virus isolates. By charting influenza virus strains in this way, it should be possible to better understand genetic and antigenic evolution.
J. C. de Jong, D. J. Smith, A. S. Lapedes, I. Donatelli, L. Campitelli, G. Barigazzi, K. Van Reeth, T. C. Jones, G. F. Rimmelzwaan, A. D. M. E. Osterhaus, R. A. M. Fouchier (2007). Antigenic and Genetic Evolution of Swine Influenza A (H3N2) Viruses in Europe Journal of Virology, 81 (8), 4315-4322 DOI: 10.1128/JVI.02458-06
D. J. Smith (2004). Mapping the Antigenic and Genetic Evolution of Influenza Virus Science, 305 (5682), 371-376 DOI: 10.1126/science.1097211