A new anti-vaxx myth has surfaced which seems to have been developed as a result of my recent blogpost Disneyland Measles Outbreak is Due to Measles which discussed the measles genotype responsible (hint: it wasn't the vaccine strain). Some, with no knowledge of virology nor immunology are spreading the myth that since the measles strain in the MMR vaccine is genotype A that it couldn't possibly protect against measles genotype B3 which is the genotype responsible for the latest U.S. outbreak and has spread to Mexico and Canada. I will discuss how and why MMR vaccines are cross-protective for wild-type measles strains.
First there is some terminology which must be understood to follow along:Serotype: Microorganisms of the same species can be further divided into serotypes, serovars or sub-groups based upon their surface antigens.
Antigen: A structural protein on the surface of a pathogen that is able to recognise cell receptors on the surface of a host cell. The antigen is also the part of the pathogen which provokes the host adaptive immune response that generates antibodies.
Epitope: The very specific part of the antigen which antibodies attach to.
Genotype: The nucleotide sequence of certain regions of a viral genome which classifies differences.
The measles virus has only one serotype and causes measles unlike Human Papillomavirus which has dozens of serotypes and can cause different diseases. This is why we see multiple serotypes included in the HPV vaccine and only one strain in each of the available measles vaccines which are all genotype A.
Many of the attenuated strains in use are derived from the Edmonston strain isolated in 1954, including the Schwartz, the Edmonston-Zagreb, and the Moraten strains. Other strains which are not derived from Edmonston strain include the CAM-70, TD 97, Leningrad-16, and Shanghai 191 (Ji-191) strains.Measles virus genotypes are based upon their nucleotide sequences at the least conserved regions of the viral genome:
Wild-type measles viruses have been divided into distinct genetic groups, referred to as genotypes, based on the nucleotide sequences of their hemagglutinin (H) and nucleoprotein (N) genes, which are the most variable genes on the viral genome.
The 450 nucleotides encoding the carboxy-terminal 150 amino acids of the nucleoprotein has up to 12% nucleotide variation between genotypes. The 450 nucleotides that encode the carboxy-terminal region of the nucleoprotein (N–450) are required for determination of the genotype. The measles genotyping protocol is available from CDC.
What this means is that whenever a measles case occurs, a sample (throat or nasal swab) is taken from the patient, submitted to RT-PCR (reverse transcription-polymerase chain reaction) and PCR (polymerase chain reaction) which are molecular techniques to essentially isolate amplify the number of DNA copies so that they can be sequenced. DNA sequencing determines the nucleotide sequences of specific genome regions and then compared to other isolates to see where the measles virus came from and also mutations that may have accumulated.
Recovered measles viruses are constantly monitored, tested and characterised to identify areas of the genome which may antigenically-drift. Circulating measles viruses have also been tested against vaccine-derived antibodies to ensure vaccines will cross-protect against the numerous genotypes that are imported. This is achieved through virus neutralisation assays for example. This is a test that combines measles genotypes with serum samples of people either vaccinated or previously infected with wild-type measles to determine if antibody binding occurs. A fluorescent tag is added and then the antibody-antigen complex is measured. Results of various assays demonstrate that vaccine-derived antibodies protect against many different measles genotypes:
The serum samples from recently vaccinated persons neutralized both the Moraten and Chicago-I viruses equally well (table 1): There was a less than 2-fold difference in neutralization titers. In contrast, serum samples from persons with a recent wild type infection were able to detect antigenic differences between the viruses. Sera in this set had neutralization titers against Chicago-l that were 4-8 times higher (average, 5.1) than the titers against the vaccine strain.Very specific antibodies called monoclonal antibodies (MAbs) are also developed and tested against measles viruses including the vaccine strains to monitor vaccine efficacy and antigenic drift of measles genotypes:
Overall, the antigenic data indicated that some epitopes have been conserved between the vaccine strain and the recent wild type viruses, while others are unique to the recent wild type virus. The H and F proteins are responsible for the induction of a neutralizing antibody response to measles virus. Therefore, the antigenic differences were most likely due to variation in these surface glycoproteins.
Protection against the current circulation measles genotype, B3 has been elucidated. In other words, studies have been and are conducted to test antibodies derived from vaccination against numerous wild-type measles viruses. Measles genotype B3 which is the currently circulating strain in the U.S., is neutralised by vaccine-derived antibodies. That, in turn, means that the virus can't bind to host (human) cell receptors and cause disease.
On the basis of the sequences of their N and H genes, MeVs can be assigned to 1 of 23 genotypes and 1 provisional genotype [11, 12]. All vaccine strains and their wild-type progenitors are assigned to genotype A. Experiments with monoclonal antibodies have defined antigenic differences between the H proteins of genotype A vaccines and the H proteins of wild-type viruses grouped in other genotypes [62, 188, 189]. However, there is only 1 serotype for measles, and serum samples from vaccinees neutralize viruses from a wide range of genotypes, albeit with different neutralization titers [188, 190] More importantly, despite the presence of different endemic genotypes, vaccination programs with standard measles vaccines have been successful in every country where they were performed adequately [191–193]. Suboptimal seroconversion after vaccination is likely the result of inadequate coverage; improper administration, transport, or storage of vaccine; or age of the vaccine recipients [194–196].It's a bit of a complex issue to digest but some key points are that measles vaccines induce many different antibodies against measles antigens. There is some antigenic drift that renders a single antibody insufficient binding to a single antigen from some wild-type measles viruses but over all, vaccines protect us from many different genotypes including the currently circulating B3 genotype. The epidemiology of the measles outbreak also demonstrates the effectiveness of the MMR vaccine. To date there have been 141 cases confirmed (dozens more reported) by the CDC. Measles is one of the most infectious diseases known and this interactive graphic demonstrates how measles can spread in variable susceptible populations. If the vaccine did not proffer cross-protection, there would be tens of thousands of cases to date. Obviously this is not the case as the majority of cases are unvaccinated.
A more easily-digestible version of this has been posted at The Scientific Parent.