Effect of Previous Respiratory Syncytial Virus Infection on Murine Immune Responses to F and G Protein-Containing Virus-Like Particles

Cullen, Lori McGinnes; Schmidt, Madelyn R.; Morrison, Trudy G.

doi:10.1128/jvi.00087-19

Cited by 13 publications

(14 citation statements)

References 45 publications

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“…An important property of vaccines is the durability of protective antibodies, but many vaccines do not result in a long duration of protection. We have previously reported that VLPs with RSV glycoproteins stimulate quite durable NAbs in mice, a result that correlates with our findings in mice of significant levels of anti-F protein splenic memory B cells and anti-F protein antibody-secreting bone marrow-associated plasma cells (41). Here we have shown a similar durability of anti-F protein antibody levels in cotton rats, as the levels of NAbs and total anti-F antibodies changed little during the 118 days after VLP immunization.…”

Section: Discussionsupporting

confidence: 92%

“…4B and C). Thus, anti-RSV F antibodies in dams do not decrease with time after VLP immunization, suggesting that the VLPs effectively stimulate cotton rat anti-F protein B cell memory and long-lived anti-F protein-secreting bone marrow-associated plasma cells induced by RSV priming, as we have previously suggested in murine studies (41). Serum titers in offspring of immunized dams.…”

Section: Durability Of Rsv Immune Responses In Damssupporting

confidence: 52%

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Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus

Blanco

Fernando

Zhang

et al. 2019

J Virol

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Maternal vaccination may be the most effective and safest approach to the protection of infants from respiratory syncytial virus (RSV) infection, a severe acute lower respiratory tract disease in infants and young children worldwide. We previously compared five different virus-like particle (VLP)-associated, mutation-stabilized prefusion F (pre-F) proteins, including the prototype DS-Cav1 F VLPs. We showed that alternative versions of prefusion F proteins have different conformations and induce different populations of anti-F protein antibodies. Two of these alternative pre-F VLPs, the UC-2 F and UC-3 F VLPs, stimulated in mice higher titers of neutralizing antibodies than DS-Cav1 F VLPs (M. L. Cullen, R. M. Schmidt, M. G. Torres, A. A. Capoferri, et al., Vaccines 7:21–41, 2019, https://doi.org/10.3390/vaccines7010021). Here we describe a comparison of these two pre-F VLPs with DS-Cav1 F VLPs as maternal vaccines in cotton rats and report that UC-3 F VLPs significantly increased the neutralizing antibody (NAb) titers in pregnant dams compared to DS-Cav1 F VLPs. The neutralizing antibody titers in the sera of the offspring of the dams immunized with UC-3 F VLPs were significantly higher than those in the sera of the offspring of dams immunized with DS-Cav1 VLPs. This increase in serum NAb titers translated to a 6- to 40-fold lower virus titer in the lungs of the RSV-challenged offspring of dams immunized with UC-3 F VLPs than in the lungs of the RSV-challenged offspring of dams immunized with DS-Cav1 F VLPs. Importantly, the offspring of UC-3 F VLP-immunized dams showed significant protection from lung pathology and from induction of inflammatory lung cytokine mRNA expression after RSV challenge. Immunization with UC-3 F VLPs also induced durable levels of high-titer neutralizing antibodies in dams. IMPORTANCE Respiratory syncytial virus (RSV) is a significant human pathogen severely impacting neonates and young children, but no vaccine exists to protect this vulnerable population. Furthermore, direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, and neonate immunization is potentially unsafe. Maternal vaccination may be the best and safest approach to the protection of neonates through the passive transfer of maternal neutralizing antibodies in utero to the fetus after maternal immunization. Here we report that immunization of pregnant cotton rats, a surrogate model for human maternal immunization, with novel RSV virus-like particle (VLP) vaccine candidates containing stabilized prefusion RSV F proteins provides significant levels of protection of the offspring of immunized dams from RSV challenge. We also found that antibodies induced by VLPs containing different versions of the prefusion F protein varied by 40-fold in the extent of protection provided to the offspring of vaccinated dams upon RSV challenge.

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Section: Discussionsupporting

confidence: 92%

Section: Durability Of Rsv Immune Responses In Damssupporting

confidence: 52%

Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus

Blanco

Fernando

Zhang

et al. 2019

J Virol

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“…Sera from each group of dams from each time point were pooled for determination of the total anti-pre-F IgG by ELISA. The levels of total anti-pre-F IgG antibodies increased significantly after a pre-F VLP or Post F VLP single immunization at day 70, as we have previously reported (18, 28, 31) (Figure 2, panels A and B) and remained relatively stable from day 141 to day 277 varying no more than 20%, with the exception of a drop at day 184 to between 43-58% of that on day 141 (Figure 2, Table 1). Day 184 was just before the delivery of the second breeding.…”

Section: Resultssupporting

confidence: 82%

“…In these studies, we have used RSV-primed animals in order to mimic normal human populations, most of which have been previously infected with RSV. We have reported that immunization of RSV-primed dams during pregnancy with pre-F VLPs resulted in robust protection of offspring from RSV challenge with no evidence of pathology (29-31). Here we describe the durability of these protective responses in dams after a single immunization and compare the degree of protection these dams can transfer to their offspring in two consecutive litters.…”

Section: Introductionmentioning

confidence: 99%

Evolution of protection after maternal immunization for respiratory syncytial virus in cotton rats

Blanco

Cullen

Kamali

et al. 2021

Preprint

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Maternal anti-respiratory syncytial virus (RSV) antibodies acquired by the fetus through the placenta protect neonates from RSV disease through the first weeks of life. In the cotton rat model of RSV infections, we previously reported that immunization of dams during pregnancy with virus-like particles assembled with mutation stabilized pre-fusion F protein as well as the wild type G protein resulted in robust protection of their offspring from RSV challenge (Blanco, et al Journal of Virology 93: e00914-19, https://doi.org/10.1128/JVI.00914-19). Here we describe the durability of those protective responses in dams, the durability of protection in offspring, and the transfer of that protection to offspring of two consecutive pregnancies without a second boost immunization. We report that four weeks after birth, offspring of the first pregnancy were significantly protected from RSV replication in both lungs and nasal tissues after RSV challenge, but protection was reduced in pups at 6 weeks after birth. However, the overall protection of offspring of the second pregnancy was considerably reduced, even at four weeks of age. This drop in protection occurred even though the levels of total anti-pre-F IgG and neutralizing antibody titers in dams remained at similar, high levels before and after the second pregnancy. The results are consistent with an evolution of antibody properties in dams to populations less efficiently transferred to offspring or the less efficient transfer of antibodies in elderly dams.

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“…We have developed novel virus-like particle (VLP) vaccine candidates for RSV [14][15][16][17][18]. In contrast to soluble proteins, VLPs robustly stimulate immune responses without the complications of adjuvant addition [19].…”

Section: Introductionmentioning

confidence: 99%

Comparisons of Antibody Populations in Different Pre-Fusion F VLP-Immunized Cotton Rat Dams and Their Offspring

et al. 2020

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Respiratory syncytial virus (RSV) infection poses a significant risk for infants. Since the direct vaccination of infants is problematic, maternal vaccination may provide a safer, more effective approach to their protection. In the cotton rat (CR) model, we have compared the immunization of pregnant CR dams with virus-like particles assembled with the prototype mutation stabilized pre-fusion F protein, DS-Cav1, as well two alternative mutation stabilized pre-fusion proteins (UC-2 F, UC-3 F) and showed that the alternative pre-fusion F VLPs protected the offspring of immunized dams significantly better than DS-Cav1 F VLPs (Blanco, et al. J. Virol. 93: e00914). Here, we have addressed the reasons for this increased protection by characterizing the specificities of antibodies in the sera of both immunized dams and their offspring. The approach was to measure the levels of total anti-pre-F IgG serum antibodies that would block the binding of representative pre-fusion specific monoclonal antibodies to soluble pre-fusion F protein targets. Strikingly, we found that the sera in most offspring of DS-Cav1 F VLP-immunized dams had no mAb D25-blocking antibodies, although their dams had robust levels. In contrast, all offspring of UC-3 F VLP-immunized dams had robust levels of these D25-blocking antibodies. Both sets of pup sera had significant levels of mAb AM14-blocking antibodies, indicating that all pups received maternal antibodies. A lack of mAb D25-blocking antibodies in the offspring of DS-Cav1 F VLP-immunized dams may account for the lower protection of their pups from challenge compared to the offspring of UC-3 F VLP-immunized dams.Vaccines 2020, 8, 133 2 of 15 to infectious, attenuated, or vector viruses, since they do not contain a genome and do not produce a spreading infection. Our VLPs are based on the core proteins of Newcastle disease virus (NDV), NP and M proteins, and they are assembled with the RSV F and G protein ectodomains fused to the transmembane and cytoplasmic domains of the NDV F and HN proteins, respectively.There has been a resurgence of interest and activity in RSV vaccine development due to the ground-breaking studies of McLellan, et al. who succeeded in solving the crystal structure of the RSV pre-fusion F protein and identifying a set of mutations in the F protein, termed DS-Cav1, which stabilized the pre-fusion form of the F protein [20,21]. We have reported that VLPs assembled with the DS-Cav1 mutant F protein stimulate, in mice and in cotton rats, neutralizing antibody titers much higher than those induced by VLPs assembled with the post-fusion F protein or wild-type F protein [16,22]. Furthermore, the immunization of cotton rat dams with DS-Cav1 F VLPs protected their offspring from RSV challenge [14].Since the description of DS-Cav1 F protein, a number of other laboratories and companies have identified different sets of mutations that reportedly stabilize the pre-fusion F protein [23][24][25][26][27][28][29]. A very important question for vaccine development is whether the different m...

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Effect of Previous Respiratory Syncytial Virus Infection on Murine Immune Responses to F and G Protein-Containing Virus-Like Particles

Cited by 13 publications

References 45 publications

Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus

Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus

Evolution of protection after maternal immunization for respiratory syncytial virus in cotton rats

Comparisons of Antibody Populations in Different Pre-Fusion F VLP-Immunized Cotton Rat Dams and Their Offspring

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