STM respiratory syncytial virus fusion pre-F subunit vaccine induces B-cell response more efficiently

Written byTang Xiaocang

Respiratory syncytial virus (RSV), a genus of pneumoviruses in the family Paramyxoviridae, causes severe illness in millions of infants, the elderly, and people with immune diseases worldwide, almost all of whom are infected with RSV before the age of two and recurrent throughout their lives, and importantly, there is currently no approved vaccine [1]
。 The F glycoprotein of RSV is highly antigenic and heritable, and it has two main conformations on the surface of RSV: active conformation, that is, pre-fusion F (pre-F) conformation; and inactive conformation, i.
e.
post-fusion F (post-F).

Pre-F has six major antigenic loci (Ø, I, II, III, IV, and V), while post-F has only four (I, II, III, and IV), the latter is more stable but not antigenic, the former is antigenic, but relatively unstable [2].

。 Both conformations have entered the clinical evaluation process as vaccine candidates, but there is currently a lack of direct comparisons
of immunity induced by pre-F and post-F vaccines.

DS-Cav1 is a stable pre-F vaccine recently evaluated in a Phase 1 clinical trial (NCT03049488) to healthy adult volunteers (18 to 50 years of age) at doses of 50, 150, or 500 micrograms supplemented with aluminum adjuvant
。 MEDI7510 is a 2% stable emulsion vaccine consisting of 120 mcg of soluble post-F adjuvant with 5 mcg glucosyl lipid adjuvant (GLA) for use in older adults (≥ 60 years of age) and in Phase 1 It was evaluated in (NCT02115815 and NCT02289820) and Phase 2b (NCT02508194) clinical trials.

On December 21, 2022, Tracy Ruckwardt of the National Institutes of Health presented an online presentation on Science Translational Medicine titled A research paper on prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine The antibody and B cell responses induced by DS-Cav1 and MEDI7510 were compared, and serological characteristics and B-cell phenotypic differences were elaborated to better understand the advantages and disadvantages of each conformation as a vaccine immunogen, providing important strategies
for future RSV vaccine design.

The investigators first evaluated RSV neutralization antibodies from serum samples from all participants before and 4 weeks after vaccination, and 4 weeks after vaccination, DS-Cav1-induced RSV A and B subtype neutralizing antibodies increased 6- to 8-fold, while MEDI7510-induced neutralization increased only 1.
5-fold
.
After overdilution of serum to MEDI7510-induced neutralizing antibodies no different from before inoculation, the neutralizing activity of DS-Cav1 against RSV A still increased by a factor of 6.
9, and these neutralizing activities were contributed
by antibodies bound to the Ø and V epitopes.
Similarly, IgG-binding antibodies increased 8- to 11-fold after 4 weeks of DS-Cav1 vaccination, and DS-Cav1 vaccination significantly stimulated pre-F-specific binding antibodies
with higher average efficacy.
The researchers also evaluated antibodies in serum that competed for pre-F binding to D25 (site O), post-F binding to Palivizumab (site II), or post-F binding to 131-2A (site I) (site I) Concentration
.
Among them, D25 competitive antibody (DCA) and Palivizumab monoclonal antibody competitive antibody (PCA) can be broadly classified as apex or laterally bound antibodies
.
The results showed an 8.
8-fold increase in DCA (apex binding antibodies) caused by DS-Cav1 vaccination, compared with 1.
9-fold for MEDI7510, with similar PCA concentrations; 6.
2-fold and 7.
4-fold
PCA concentrations for 1CA, respectively.
These data suggest that DS-CAV1 vaccination elicited powerful apex and laterally bound antibodies
.
MEDI7510 vaccination resulted in antibodies against lateral epitopes and higher titers of antibodies
competing with 131-2A.

Subsequently, the researchers evaluated the memory B cell response
induced by vaccination with DS-Cav1 or MEDI7510.
Using fluorescently labeled pre-F and post-F probes, memory B cells
are stream-gated with CD19+CD38- and CD20+IgD- as the gate 。 In the first week after vaccination, DS-Cav1 elicited pre-F tendency and pre-F&post-F double-binding IgG+ and IgA+ B cell responses, while MEDI7510 caused post-F tendencies and double-bound B cell responses, and after DS-Cav1 vaccination, pre-F had a higher frequency of IgG+ and IgA+ B cells compared to MEDI751, but the frequency of double-bound B cells induced by both
。 Activated memory B cells (ABCs) assays showed that prior to inoculation, 65% to 88% of probe-bound IgG+ B cells were predominantly CD21+CD27+ quiescent memory phenotypes in all F specificities, and one week after DS-Cav1 vaccination, 94.
9% of pre-F tendencies and 93.
3% of double-bound IgG+ B cells had reduced CD21 expression and increased CD71 expression by 81.
9% Post-F tends to be activated by IgG+ B cells, and IgA+ B cells respond similarly
.
Conversely, after MEDI7510 vaccination, IgG+ B cells, which were predominantly double-bound and post-F-inclined to IgG+, were activated, 88.
1% and 81.
9%, respectively, and only 24.
7% of pre-F-prone B cells exhibited an activated phenotype
.
Together, these results suggest that DS-Cav1 vaccination promotes the activation and proliferation of memory B cells targeting the most neutral and sensitive sites, further underscores the importance of F conformation in RSV vaccine design, and supports the development and production
of pre-F vaccines.

Overall, the researchers evaluated the effect of RSV fusion protein (F) conformation on B cell responses, comparing samples from DS-Cav1 (pre-F) and MEDI7510 (post-F) vaccine clinical trials.
Assess the strength and quality
of serological and B-cell responses at different time points.
The results showed that both DS-Cav1 and MEDI7510 vaccination caused F-specific antibodies and B cells, but the antibodies caused by DS-Cav1 had a stronger neutralizing effect on RSV A and B
.
In terms of memory (CD27+) B cells, pre-F-prone B cells were significantly activated after DS-Cav1 inoculation, but not MEDI7510 vaccine, and the findings highlight the importance of
using pre-F as an immunogen in humans.

It is worth noting that Science Translational Medicine published a contemporaneous focus affirming the importance of
pre-F protein as a vaccine immunogen.