Longitudinal study of the immune response and memory following natural bovine respiratory syncytial virus infections in cattle of different age

Human and bovine respiratory syncytial virus (HRSV and BRSV) are closely genetically related and cause respiratory disease in their respective host. Whereas HRSV vaccines are still under development, a multitude of BRSV vaccines are used to reduce clinical signs. To enable the design of vaccination protocols to entirely stop virus circulation, we aimed to investigate the duration, character and efficacy of the immune responses induced by natural infections. The systemic humoral immunity was monitored every two months during two years in 33 dairy cattle in different age cohorts following a natural BRSV outbreak, and again in selected individuals before and after a second outbreak, four years later. Local humoral and systemic cellular responses were also monitored, although less extensively. Based on clinical observations and economic losses linked to decreased milk production, the outbreaks were classified as moderate. Following the first outbreak, most but not all animals developed neutralising antibody responses, BRSV-specific IgG1, IgG2 and HRSV F- and HRSV N-reactive responses that lasted at least two years, and in some cases at least four years. In contrast, no systemic T cell responses were detected and only weak IgA responses were detected in some animals. Seronegative sentinels remained negative, inferring that no new infections occurred between the outbreaks. During the second outbreak, reinfections with clinical signs and virus shedding occurred, but the signs were milder, and the virus shedding was significantly lower than in naïve animals. Whereas the primary infection induced similar antibody titres against the prefusion and the post fusion form of the BRSV F protein, memory responses were significantly stronger against prefusion F. In conclusion, even if natural infections induce a long-lasting immunity, it would probably be necessary to boost memory responses between outbreaks, to stop the circulation of the virus and limit the potential role of previously infected adult cattle in the chain of BRSV transmission

Longitudinal study of the immune response and memory following natural bovine respiratory syncytial virus infections in cattle of different age

International audienceHuman and bovine respiratory syncytial virus (HRSV and BRSV) are closely genetically related and cause respiratory disease in their respective host. Whereas HRSV vaccines are still under development, a multitude of BRSV vaccines are used to reduce clinical signs. To enable the design of vaccination protocols to entirely stop virus circulation, we aimed to investigate the duration, character and efficacy of the immune responses induced by natural infections. The systemic humoral immunity was monitored every two months during two years in 33 dairy cattle in different age cohorts following a natural BRSV outbreak, and again in selected individuals before and after a second outbreak, four years later. Local humoral and systemic cellular responses were also monitored, although less extensively. Based on clinical observations and economic losses linked to decreased milk production, the outbreaks were classified as moderate. Following the first outbreak, most but not all animals developed neutralising antibody responses, BRSV-specific IgG1, IgG2 and HRSV F- and HRSV N-reactive responses that lasted at least two years, and in some cases at least four years. In contrast, no systemic T cell responses were detected and only weak IgA responses were detected in some animals. Seronegative sentinels remained negative, inferring that no new infections occurred between the outbreaks. During the second outbreak, reinfections with clinical signs and virus shedding occurred, but the signs were milder, and the virus shedding was significantly lower than in naïve animals. Whereas the primary infection induced similar antibody titres against the prefusion and the post fusion form of the BRSV F protein, memory responses were significantly stronger against prefusion F. In conclusion, even if natural infections induce a long-lasting immunity, it would probably be necessary to boost memory responses between outbreaks, to stop the circulation of the virus and limit the potential role of previously infected adult cattle in the chain of BRSV transmission

Kinetics of BRSV-neutralising serum antibody titres in cattle of different age and production status.

Cattle were (A) 23–30 months old (6.5 months gestation), (C) 7–11 months old, (D) 4–5 months old, (E) 2–3 months old, not analysed (N.A), or (F) born during or just after a BRSV outbreak in January 2016 (month 0). Limit of detection in the virus neturalising assay: titre 20.</p

Kinetics of BRSV-specific total IgG1 in milk from cattle of different age and production status.

At the time of a BRSV outbreak (in January 2016, month 0) the cattle were (A) 23–30 months old (6.5 months gestation), or (C) 7–11 months old. Corrected optical density (COD) values are presented as percentage of a positive control serum. Broken lines represent dry periods and red circles are timepoints for calving.</p

Kinetics of HRSV-F-reactive serum antibodies in cattle of different age and production status.

At the time of a BRSV outbreak the cattle were (A) 23–30 months old (6.5 months gestation), (C) 7–11 months old, (D) 4–5 months old, (E) 2–3 months old, or (F) born during or just after the outbreak in January 2016 (month 0). Data are presented as competition percentage. The limit of detection is presented as a dotted line.</p

Least Square Means of milk production, roughage and non-roughage intake of 272, 163 and 272 cows, respectively, that remained in production for commercialisation, before, during and after a BRSV outbreak in 2016.

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Kinetics of HRSV N-specific serum IgG1 antibodies in cattle of different age and production status.

At the time of a BRSV outbreak the cattle were (A) 23–30 months old (6.5 months gestation), (C) 7–11 months old, (D) 4–5 months old, (E) 2–3 months old, or (F) born during or just after the outbreak in January 2016 (month 0). For each serum sample, the optical density (OD) against a control antigen was subtracted from the OD value against the N protein (Corrected OD, COD) and the COD was transformed into a sample-to-positive value (SP) by using the formula SP = CODsample/(CODpos—CODneg).</p

BRSV RNA detected in nasal swabs of cows that were naturally re-infected four years after a previous natural BRSV infection (n = 7, reinfection) and cows that were naturally infected for the first time (n = 5).

Samples were collected once and on the same day. All cows were housed in the same section of the loose range system. The unit TCID50 equivalent (TCID50 eq.) was used since the standard curve used in the assay was based on a BRSV-infected cell lysate with a known titre. Error bars represent standard deviation. (TIF)</p

Sampling for BRSV diagnosis and monitoring of BRSV-specific immunity.

Sampling for BRSV diagnosis and monitoring of BRSV-specific immunity.</p

BRSV-specific serum antibodies in naïve cows and in cows infected with BRSV four years earlier.

BRSV-neutralising antibodies (VN), BRSV-Pre F-specific IgG1 antibodies (Pre F) and BRSV-Post F-specific IgG1 antibodies (Post F), AM14-competing antibodies reactive to Pre F (AM14) and BRSV-specific IgG1 (BRSV lysate) 3 weeks before a BRSV (re)infection (March 2020). Animal 355–636 had been infected four years earlier (January 2016).</p