The Implications of the Rubella Virus in Un-vaccinated Pregnant Women, and Alternative Vaccine Prototypes

The rubella virus is from the Togaviridae family and the genus of rubivirus. It is an enveloped, single-stranded, positive-sense RNA virus consisting of about 9762 nucleotides, and containing two envelope glycoproteins, E1 and E2, and a capsid (C) protein (refer to Figure 1) (Petrova, et al., 2016). Glycoprotein E1 is a structural surface protein, which contains a fusion peptide that aids in the viral entry into the host cells, and it is also known for its interaction with the other glycoprotein, E2 (Petrova, et al., 2016). Rubella virus enters the host cells via receptor-mediated endocytosis (Flint, et al., 534, 2015). Each of the E1 epitope regions (~208-239 amino acids), or the antigens that are capable of eliciting the immune response, exhibit hemagglutinating and neutralizing activities against antibody production (refer to Figure 2) (Petrova, et al., 2016). The glycoprotein E2 is connected to the glycoprotein E1, and is also responsible for viral entry into the host cell and virus budding from the host cell. Another important function of the glycoprotein E2 is that upon entering the cell, it undergoes a conformational change which activates the acidification of the vesicle by the glycoprotein E1, which enables the release of the viral genome into the cytoplasm of the host cell (Petrova, et al., 2016). The C protein is mainly responsible for assembling the nucleocapsid, preventing the host cell’s proteins from functioning, and has been known to initiate cell death (Petrova, et al., 2016).

Figure 1. Diagram of rubella-virus virion showing the E1 (blue) and E2 (magenta) glycoproteins, the capsid protein (yellow) and the genomic RNA (red).

Figure 2. The functional epitopes in the rubella virus E1 region (202-285 amino acids).

 

Rubella (or the “German Measles”) is the result of infection from the rubella virus. Symptoms of rubella include a low fever, and a rash that starts on the individual’s face and spreads throughout the body. Some victims may also experience swollen glands and an achiness of the joints (Rubella, CDC, 2014). Rubella can be a transplacental infection, or an infection that is passed from mother to fetus via the placenta (Flint, et al., 47, 2015). Pregnant women infected with the virus may transmit fetal defects that can arise from Congenital Rubella Syndrome (CRS). Congenital Rubella Syndrome can affect the fetus and cause the following birth defects and associated complications: Eye problems (i.e., cataracts, glaucoma, and retinitis); congenital heart disease; hearing loss; microcephaly; bone disease; mental disabilities; and diabetes (Petrova, et al., 2016). “The risk of fetal infection in infants whose mothers were infected with rubella virus during the first trimester is approximately 80%” (Flint, et al., 47, 2015). It is likely that 100,000 infants will be born with CRS every non-epidemic year (Petrova, et al., 2016).

The spread of the rubella virus is relatively commonplace as it can be contracted by an individual if he/she comes into contact with a surface infected by the rubella virus. Transmission typically occurs through the release of respiratory aerosols by the coughing or sneezing of an already-infected individual (Rubella, CDC, 2014). The development of the MMR vaccine helped to eradicate the issue of CRS for its recipients. It is recommended that children should receive two doses of M.M.R. vaccine to ensure the long-lasting immunization against the measles virus (Rubella, CDC, 2014). Children typically receive their first dose of vaccination at 12 months of age, then later receive a second dose at five to six years of age (Haberman, 2015).

Those females who were not previously vaccinated cannot receive the vaccine, due to the live virus, while already pregnant (Petrova, et al., 2016). The Measles-Mumps-Rubella (M.M.R.) vaccine uses the live-attenuated strain RA27/3 and is often combined with other viral particles to ensure immunity for measles and mumps as well as rubella (Petrova, et al., 2016). Petrova et al. discusses some alternative vaccine options that are in the works against the rubella virus by focusing mainly on the glycoprotein E1. These options may help those individuals who may not suitable for inoculation with the MMR vaccine, such as pregnant women, individuals with AIDs or other individuals with immunodeficiency-related issues.

Rubella viral immunity occurs when the anti-E1 antibodies are neutralized, so many of the candidate vaccines are targeting the E1 glycoprotein, in order to develop a non-replicating, recombinant vaccine. Pougatcheva et al. constructed the rubella-virus DNA vaccine by amplifying the rubella viral genome sequence coding for the capsid protein and glycoproteins E1 and E2 (categorized as CE1E2), and another genome sequence coding for solely the glycoproteins E1 and E2 (categorized as E1E2) (Pougatcheva, et al., 1999). Once the rubella-virus DNA vaccine was infused in the mice trial subjects, neutralizing activity was detected and they demonstrated that the antibody production was mainly directed against the E1 glycoprotein than any other proteins (refer to Figure 3) (Pougatcheva, et al., 1999). A booster injection was also found to increase antibody production and increase effectiveness of vaccine when injected 4 weeks after the initial injection (refer to Figure 3).

These rubella-virus DNA vaccines are currently considered to be only prototypes, but may prove to be advantageous to pregnant, unvaccinated women in future generations because they do not involve the use of the attenuated live strain of RA27/3 (Pougatcheva, et al., 1999). The neutralizing titers induced by mice with the DNA vaccine (1:2 to 1:8) was similar to that of the neutralizing titers induced by the mice that were immunized with the RA27/3 strain (1:2) (Pougatcheva, et al., 1999). The longevity of this antibody response from this non-replicating alternative vaccine seems encouraging, so long as it produces the same response in humans as it has produced for mice (Pougatcheva, et al., 1999)

Figure 3. Antibody response induced by DNA vaccine constructs. Groups of ten eight-week old Balb/C mice were immunized with pVR/E2E1 (E2E1), pVR/CE2E1 (CE2E1), or pVR (VR) and groups of five mice were immunized intramuscularly with 107 pfu of rubella virus (RV) or not immunized (C). Half of the mice in each DNA vaccine group were boosted (B) and half were not boosted (NB) four weeks after initial immunization; the RV- and C-mice were not boosted. Serum was collected from all mice (both boosted and nonboosted) at 8 weeks and again at 7 months.

References

Flint, J., V.R. Racaniello, G.F. Rall, & A.M. Skalka. (2015). Volume I: Principles of Virology. Washington, DC: ASM Press, 534-5.

Flint, J., V.R. Racaniello, G.F. Rall, & A.M. Skalka. (2015). Volume II: Principles of Virology. Washington, DC: ASM Press, 47.

Haberman, C. (2015, February 1). A Discredited Vaccine Study’s Continuing Impact on Public Health. The New York Times. Retrieved from http://www.nytimes.com/2015/02/02/us/a-discredited-vaccine-studys-continuing-impact-on-public-health.html.

Petrova, E.K., A.A. Dmitrieva, E.A. Trifonova, N.A. Nikitin, & O.V. Karpova. (2016). The key role of rubella virus glycoproteins in the formation of immune response, and perspectives on their use in the development of new recombinant vaccines. Vaccine 34 (1) 1006-1011.

Pougatcheva, S.O., E.S. Abernathy, A.N. Vzorov, R.W. Compans, & T.K. Frey (1999). Development of a rubella virus DNA vaccine. Vaccine 17, 2104-2112.

Rubella. (2014, December 17). Centers for Disease Control and Prevention. Retrieved January 27, 2016, from http://www.cdc.gov/rubella/about/index.html.