Analysis of virus and host factors in a study of A/Peking/2/79 (H3N2) cold‐adapted vaccine recombinant in which vaccine‐associated illness occurred in normal volunteers

Abstract

Live attenuated cold-adapted influenza vaccine is undergoing evaluation in man. Several strains have proven to be safe, immunogenic, nontransmissible, and protective against experimental challenge. In this study of A/Peking/2/79(H3N2), with six internal genes from the cold-adapted (Ca) parent A/Ann Arbor/6/60(H2N2), we encountered at the highest input multiplicity, 28% illness rate among individuals infected with vaccine. Reversion to wild type and excessive viral replication did not occur. Physical characteristics of the vaccine were similar to nonreactogenic vaccine A/Washington/897/80(H3N2). At ten- and 100-fold lower input multiplicities, infection frequency was maintained, but reactions did not occur. We compared the observations in this study with those made in a similar study of A/Scotland/840/74(H3N2), a cold-adapted vaccine with five genes from the Ca parent in which reactogenicity also was noted. The dose of vaccine virus in relation to tissue culture infectious doses required to infect 50% of susceptibles (HID50) was proportionally lower for both A/Peking/2/79(H3N2) and A/Scotland/80(H3N2). Hence, when the vaccine was undiluted the recipients were inoculated with more than 100 HID50. We concluded that the very high input could be avoided if vaccines were screened beginning at 1/1,000 of maximum titers. Ca vaccines must be safe before they undergo field trials.

A multi-valent vaccine approach that elicits broad immunity within an influenza subtype

“…S2). Studies in both ferrets and humans report monovalent LAIV preparations containing 10 7.6 –10 9.0 TCID 50 show increased incidence of febrile responses [63–65], and similar to our results, the human studies report elimination of the adverse effect after a one log reduction in the inoculation dose [64,65]. …”

A Randomized, Double-Blind Study of the Safety, Transmissibility and Phenotypic and Genotypic Stability of Cold-Adapted Influenza Virus Vaccine

“…Historical data for early investigational versions of LAIV collected during the past 3 decades indicate that the mean peak titer of vaccine virus recovered from nasal secretions of young children is generally Յ4 logs per milliliter and for adults is Յ2 logs per milliliter, and the median human infectious dose in children is approximately 2.5 to 4.6 logs and in adults is approximately 4.9 to 6.4 logs for vaccine virus. 10,13,16,18,19,[22][23][24][25][26][27][28][29][30] These data predict that adults would be unlikely to transmit to other adults and that young children would be unlikely to transmit to adults. As observed in this trial, children in settings such as day care may shed enough vaccine virus to infect other young children.…”

Principles Underlying the Development and Use of Live Attenuated Cold-Adapted Influenza A and B Virus Vaccines

“…This represents about 40 HID 50 's for seronegative adults and 400 for immunologically naive infants and children. When doses higher than 10 7.0 TCID 50 are given, febrile systemic illness can occur in the absence of a high level of virus replication, indicating that there is an upper limit of dose that is acceptable for use in humans (9). Doses below 10 7.0 TCID 50 are not optimally infectious for seronegative adults and also not optimally immunogenic for young infants.…”

“…Phenotypic stability of the influenza A ca reassortant viruses following replication in vivo. The ts and ca phenotypes of the A/AA/6/60 ca reassortants have been very stable following replication in humans (1,9,14,20,34,51,62,63,67,81,82) (Table 3). The observation that the ts and ca phenotypes of 11 H3N2 or H1N1 ca reassortants were phenotypically stable indicates that transfer of the six genes of the influenza A/AA/6/60 ca donor virus reproducibly confers these two phenotypes to its 6/2 gene ca reassortants.…”