Measles Vaccination: New Strategies and Formulations

Rory D de Vries; Koert J Stittelaar; Albert DME Osterhaus; Rik L de Swart

Disclosures

Expert Rev Vaccines. 2008;7(8):1215-1223. 

In This Article

New-generation Vaccine Formulations

Several alternative MV vaccine formulations have been evaluated over the last few decades, as summarized in a previous review.[52] Here, we will focus on new developments and update the previous overview of published MV vaccine studies Table 2 .

DNA Vaccines

DNA vaccines are considered to be a potential alternative formulation to the currently used LAV. Advantages are that a cold chain may not have to be maintained, it has been suggested not to interfere with a later LAV boost[53] and it is possible to vaccinate in the presence of maternal antibodies. Several studies with DNA vaccines have been performed in mice[54–56] and cotton rats.[57] DNA plasmids expressing MV-hemagglutinin protien (H), fusion protien (F) and nucleoprotein (N) were capable of inducing humoral and cellular immune responses in these animals to a varying extent. In cotton rats, DNA vaccination did not induce immune responses in the presence of maternal antibodies and challenge experiments showed limited protection.[57]

Multiple studies were performed in macaques with DNA plasmids encoding MV-H, -F and -N. A study performed by Polack et al. showed that DNA vaccination with plasmids encoding MV-H was safe and did not predispose to atypical measles.[58] Furthermore, it was shown that immunization with MV-H led to a type-2 immune response, whereas MV-F primed for a type-1 response; combining MV-F and -H led to a more modulated immune response.[59] A DNA plasmid encoding MV-F, -H and -N was tested in the presence of maternal antibodies.[60] After passive transfer of MV-specific immunoglobulin, macaques were vaccinated twice with an 8-week interval and challenged with wild type-MV after 20 weeks. The vaccine efficiently induced cell-mediated immunity, and 16 out of 25 macaques reached protective neutralizing antibody titers. Upon challenge, reduced viremia and partial protection from disease was observed.[60] The addition of IL-2 as an adjuvant for vaccination seemed especially beneficial for protection from clinical signs upon challenge.[61] Combined, these macaque studies show that DNA vaccination can lead to both humoral and cellular immune responses, is safe and partially protects against subsequent MV infection in the absence and presence of passively transferred MV-specific antibodies. However, humoral immune responses induced are low and vaccination does not lead to seroconversion in all animals.

Recent studies have focused on the use of a Sindbis replicon-based DNA vaccine, which shows promising results. Sindbis replicons represent a new generation of immunogenic DNA vaccines,[62,63] which can be used in the presence of maternal antibodies.[64] In addition to this, they may include other gene sequences that engage the immature immune system of young infants.[65–67] In mice, vaccination with a Sindbis vaccine encoding MV-F, -H or a combination of both, was capable of inducing neutralizing antibodies [68]; the MV-H vaccine alone could do so in the presence of maternal antibodies.[69] A promising approach with this Sindbis-based vaccine was reported in 2007, when macaques produced high levels of neutralizing antibodies after intradermal vaccination with a Sindbis replicon-based vaccine encoding MV-H or -F and boosting with LAV administered as an aerosol. Infant macaques vaccinated with Sindbis MV-H and boosted with LAV were completely protected from challenge.[70] Toxicity and biodistribution studies in rabbits revealed only few and minor adverse events.[71] Recently, the Sindbis-based vaccine was adsorbed onto polylactide glycolide (PLG) microparticles. This adjuvant is capable of delivering DNA and activating antigen-presenting cells, increasing DNA persistence and recruiting mononuclear cells to the site of injection.[72] A study by Pan et al. showed that adsorption of the Sindbis vaccine onto PLG led to improved antibody and T-cell responses in mice. In the same study, however, intramuscularly vaccinated macaques were only partially protected from clinical signs and viremia upon challenge. Furthermore, low-dose intradermally vaccinated animals developed more severe rash and clinical signs, raising some concerns regarding the safety of this adjuvant.[73] More recently, the same authors identified Vaxfectin® as a promising adjuvant for measles DNA vaccination: it was found to increase neutralizing antibody responses and provided protection to juvenile and infant rhesus macaques.[74] However, at present no safety data are available for measles DNA vaccines formulated with this adjuvant.

Vector Vaccines

The use of attenuated viruses or bacteria as vectors for delivering MV antigens is another promising approach. Recombinant modified vaccinia virus Ankara was shown to be a potential candidate, and was immunogenic in macaques.[75] However, conflicting results were obtained when macaques were vaccinated in the presence of maternal antibodies,[75,76] and no more follow-up studies have been performed. Other vectors under research include vesicular stomatitis virus, Shigella flexnera and Salmonella enterica serovar Typhi,[77,78] but none of these have yet been tested in a macaque model.

Plant-based Protein

Recently, some advances were made with a plant-based candidate oral vaccine. Plant-based MV-H recombinant protein vaccines were prepared in transgenic tobacco, carrot or lettuce. Mice vaccinated intraperitoneally with recombinant protein produced low levels of MV-neutralizing antibodies, but multiple doses were always required.[79–82] Similar results were observed with oral administration.[79,81] These studies also showed that oral application of multiple recombinant protein doses are efficient in inducing humoral immune responses as a booster after a primary DNA vaccination.[81,83] Oral vaccination alone does not seem to induce high neutralizing antibody titers, and challenge experiments in macaques need to be performed to examine protection and possible adverse effects. In addition, multiple oral doses with the same antigen might lead to the induction of tolerance and, therefore, be ineffective.

Protollin-adjuvanted Antigen

A new potential adjuvant efficient for mucosal vaccination is protollin, which is a proteasome-based adjuvant containing immuno­stimulatory proteins.[84] A combination vaccine of protollin with MV-H and MV-F was immunogenic in mice when two doses were administered intranasally.[85] In macaques, three doses were needed to reach protective levels of neutralizing antibodies, and protollin-MV could also be used as a boost after DNA vaccine priming.[70]

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