From the Journals

New RSV vaccine immunogenicity improved with protein engineering



Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.

vaccine vials Micah Young/

The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.

“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.

Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.

“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.

But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.

In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.

The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.

The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.

Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).

“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).

Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).

“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.

The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.

The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”

The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.

SOURCE: Crank MC et al. Science. 2019; 365(6452):505-9.

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