Fig. 1. Screening, enrollment, and follow-up of RSV-seropositive children and RSV-seronegative children in the phase 1 clinical trial of the RSV MEDI Δ M2-2 vaccine. (A) RSV-seropositive children. (B) RSV-seronegative children. As described in the text, we initiated the study with administration of the RSV MEDI Δ M2-2 vaccine to 15 adults in an open-label evaluation. For this portion of the study, 31 adults were screened, 19 were eligible, 15 were enrolled, and none were lost to follow-up.
Fig. 2. Proportions of RSV-seronegative vaccinees and placebo recipients with indicated illnesses. Vaccinees are shown in blue; placebo recipients are shown in red. The placebo recipient (twin B) infected with vaccine virus is not included. Fever occurred in 4 of 20 vaccinees (1 of grade 0 severity, 1 of grade 2 severity, and 2 of grade 3 severity) and in 2 of 9 placebo recipients (both of grade 2 severity): grade 0, <38°C; grade 1, ≥38°C but ≤38.6°C; grade 2, ≥38.7°C but ≤39.1°C; grade 3, ≥39.2°C but ≤40.5°C. The two episodes of grade 3 fever in vaccinees occurred on days 24 to 26 after vaccination, when shedding of vaccine virus was not detected. URI (rhinorrhea) occurred in 17 of 20 vaccinees and 4 of 9 placebo recipients; cough occurred in 7 of 20 vaccinees and 3 of 9 placebo recipients; all of these illnesses were of grade 1 severity (that is, not requiring medical attention). An episode of OM (grade 2 severity) occurred in a single vaccinee.
Fig. 3. Vaccine virus shedding and serum RSV neutralizing antibody responses in seronegative recipients of RSV MEDI ΔM2-2 or rA2 cp248/404/1030/ΔSH. NW and serum specimens from the present study were evaluated for vaccine virus titer and serum neutralizing antibodies, respectively. Antibody testing was performed in parallel with specimens from the previous clinical evaluation of rA2 cp248/404/1030/ΔSH (8). (A) Peak viral titer (expressed as log10 PFU/ml). (B) RSV PRNTs, expressed as 1/log2. *P = 0.005; +P = 0.002 (Student’s t test).
Fig. 4. Reverse cumulative distribution of RSV PRNT in seronegative vaccinees. The blue solid line represents vaccinees, and the red dashed line represents placebo recipients. Antibody titers are expressed as 1/log2, but for ease of interpretation, the titer corresponding to the arithmetic value of 1:64, achieved by 85% of vaccinees, is also shown.
Fig. 5. Rises in RSV PRNT during the surveillance period. RSV PRNT in sera from six vaccinees and three placebo recipients in whom ≥4-fold rises in titer between the pre- and postsurveillance specimens were detected (see text for additional details). Blue solid lines, vaccinees with rises in RSV PRNT in whom no RSV MAARI was detected (n = 5; corresponding to subjects 33, 35, 44, 46, and 56 in the supplementary tables); blue dashed line, vaccinee with rise in RSV PRNT in whom RSV MAARI was detected (n = 1; subject 38 in the supplementary tables); red solid line, placebo recipient with rise in RSV PRNT in whom no RSV MAARI was detected (n = 1; subject 36 in the supplementary tables); red dashed lines, placebo recipients with rise in RSV PRNT in whom RSV MAARI was detected (n = 2; subjects 43 and 57 in the supplementary tables). Antibody titers are expressed as 1/log2, but for ease of interpretation, titers corresponding to the arithmetic values of 1:16, 1:64, 1:256, 1:1024, and 1:4096 are also shown.
- Table 1. Replication of vaccine virus and clinical assessment in adults, RSV-seropositive children, and RSV-seronegative children.
NT, not tested.
Viral detection
(culture)Viral detection
(qPCR)% with indicated illness* Subjects Dose
(log10
PFU/ml)No. of
subjects%
Infected% Shedding
virus†Peak titer mean
(SD) log10
PFU/mlPeak copy
number log10
(SD)Fever URI LRI Cough OM Respiratory
or febrile
illnessOther Adults Vaccinees 6.0 15 0 0 0.6 (0.0) NT 0 20 0 7 0 20 27 Seropositive children Vaccinees 6.0 10 10 0 0.6 (0.0) NT 0 40 0 0 0 40 20 Placebo
recipientsPlacebo 5 20 0 0.6 (0.0) NT 0 0 0 0 0 0 60 Seronegative children Vaccinees 5.0 20 95 85 1.5 (0.9) 3.4 (0.9) 20 85 0 35 5 85 45 Infected
placebo
recipient‡Placebo 1 100 100 2.0 (0.0) 3.3 (0.0) 100 100 0 0 0 100 0 Placebo
recipientsPlacebo 9 0 0 0.6 (0.0) 1.7 (0.0) 22 44 0 33 0 67 78 *Illness abbreviations and definitions are as described in the text. URI was defined as rhinorrhea, pharyngitis, or hoarseness, and LRI was defined as wheezing, rhonchi, or rales, or having been diagnosed with pneumonia or laryngotracheobronchitis (croup).
†% Shedding vaccine virus as detected by culture and/or rRT-qPCR. The limit of detection of vaccine virus was 0.6 log10 PFU/ml by culture, and 1.7 log10 copy numbers/ml by rRT-qPCR.
‡Data from the seronegative placebo recipient, as described in the text.
- Table 2. Replication of vaccine virus and antibody responses in adults, RSV-seropositive children, and RSV-seronegative children.
ELISA, enzyme-linked immunosorbent assay.
Serum RSV neutralizing
antibody* [mean(SD)]Serum IgG ELISA RSV F*
[mean (SD)]Subjects Dose (log10
PFU/ml)No. of
subjects%
Infected% Shedding
virus†Pre
(SD)Post
(SD)≥4-Fold rise
(%)Pre
(SD)Post
(SD)≥4-Fold rise
(%)Adults Vaccinees 6.0 15 0 0 9.3 (1.1) 9.6 (0.9) 0 15.1 (1.2) 15.0 (1.2) 0 Seropositive children Vaccinees 6.0 10 10 0 7.5 (1.9) 7.7 (1.8) 0 14.2 (2.3) 14.0 (2.1) 10 Placebo recipients Placebo 5 20 0 8.4 (2.7) 9.0 (2.9) 20 14.8 (1.1) 15.6 (1.4) 20 Seronegative children Vaccinees 5.0 20 95 85 2.7 (0.9) 6.6 (1.1) 95 7.1 (2.7) 13.6 (1.6) 90 Infected placebo
recipient‡Placebo 1 100 100 2.3 (0.0) 7.6 (0.0) 100 5.6 (0.0) 13.6 (0.0) 100 Placebo recipients Placebo 9 0 0 2.3 (0.0) 2.3 (0.0) 0 5.4 (1.5) 5.1 (1.0) 0 *Antibody data are expressed as reciprocal mean log2 titers.
†% Shedding vaccine virus as detected by culture and/or rRT-qPCR. The limit of detection of vaccine virus was 0.6 log10 PFU/ml.
‡Data from the seronegative placebo recipient, as described in the text.
Supplementary Materials
Additional Files
- Supplementary Material for:
A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children
Ruth A. Karron,* Cindy Luongo, Bhagvanji Thumar, Karen M. Loehr, Janet A. Englund, Peter L. Collins, Ursula J. Buchholz
*Corresponding author. E-mail: rkarron{at}jhu.edu
Published 4 November 2015, Sci. Transl. Med. 7, 312ra175 (2015)
DOI: 10.1126/scitranslmed.aac8463This PDF file includes:
- Source data
