Limits...
Transient humoral protection against H5N1 challenge after seasonal influenza vaccination of humans.

Roozendaal R, Tolboom J, Roos A, Riahi S, Theeuwsen J, Bujny MV, Klaren V, Korse HJ, Dekking L, Grootenhuis A, Weverling GJ, Koudstaal W, Goudsmit J, Radošević K - PLoS ONE (2014)

Bottom Line: This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays.Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations.In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.

View Article: PubMed Central - PubMed

Affiliation: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Crucell Holland BV, Leiden, the Netherlands.

ABSTRACT
Current influenza vaccines are believed to confer protection against a narrow range of virus strains. The identification of broadly influenza neutralizing antibodies (bnAbs) has triggered efforts to develop vaccines providing 'universal' protection against influenza. Several bnAbs were isolated from humans recently vaccinated with conventional influenza vaccines, suggesting that such vaccines could, in principle, be broadly protective. Assessing the breadth-of-protection conferred to humans by influenza vaccines is hampered by the lack of in vitro correlates for broad protection. We designed and employed a novel human-to-mouse serum transfer and challenge model to analyze protective responses in serum samples from clinical trial subjects. One dose of seasonal vaccine induces humoral protection not only against vaccine-homologous H1N1 challenge, but also against H5N1 challenge. This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays. Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations. Strategies to increase the breadth and duration of the protective response against influenza are required to obtain 'universal' protection against influenza by vaccination. In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.

Show MeSH

Related in: MedlinePlus

Serum VNA titers correlate with protection against H1N1 but not H5N1 challenge.VNA titers against (A) A/California/07/2009 (H1N1) and (C) A/Hong Kong/156/97 (H5N1) were determined. Titers for mice that survive challenge (open squares) and mice that succumb to infection (closed squares) are presented separately for pre-vaccination (pre) and post-vaccination (post) sera. Assay background level is indicated with dashed line in panels A and C. Vaccine homologous H1 VNA titers are higher in post-vaccination serum (p<0.001, t-test). H5 VNA titers are detectable in some pre-vaccination samples and are higher in post-vaccination serum (p<0.001, t-test). ROC curves were calculated to assess the correlation (B) between H1N1 A/California/07/2009 VNA and protection against H1N1 A/Netherlands/602/2009 challenge and (D) between H5N1 A/Hong Kong/156/97 VNA and protection against H5N1 A/Hong Kong/156/97 challenge. H1N1 VNA correlates with protection against homologous H1N1 challenge (ROC area = 0.80, p<0.05, 95% CI 0.66–0.94). The positive correlation between H5 VNA and H5 protection does not reach statistical significance (ROC area = 0.66, 95% CI = 0.496–0.82).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4116209&req=5

pone-0103550-g004: Serum VNA titers correlate with protection against H1N1 but not H5N1 challenge.VNA titers against (A) A/California/07/2009 (H1N1) and (C) A/Hong Kong/156/97 (H5N1) were determined. Titers for mice that survive challenge (open squares) and mice that succumb to infection (closed squares) are presented separately for pre-vaccination (pre) and post-vaccination (post) sera. Assay background level is indicated with dashed line in panels A and C. Vaccine homologous H1 VNA titers are higher in post-vaccination serum (p<0.001, t-test). H5 VNA titers are detectable in some pre-vaccination samples and are higher in post-vaccination serum (p<0.001, t-test). ROC curves were calculated to assess the correlation (B) between H1N1 A/California/07/2009 VNA and protection against H1N1 A/Netherlands/602/2009 challenge and (D) between H5N1 A/Hong Kong/156/97 VNA and protection against H5N1 A/Hong Kong/156/97 challenge. H1N1 VNA correlates with protection against homologous H1N1 challenge (ROC area = 0.80, p<0.05, 95% CI 0.66–0.94). The positive correlation between H5 VNA and H5 protection does not reach statistical significance (ROC area = 0.66, 95% CI = 0.496–0.82).

Mentions: Therefore, we also determined the neutralizing activity of the serum samples against A/California/07/2009 (H1N1) and A/Hong Kong/156/97 (H5N1) viruses using a virus neutralization assay (VNA) (Fig. 4). In contrast to the HAI assay, the VNA assay is not selectively sensitive for the activity of antibodies that target the head region of HA, but is also able to detect the activity of any neutralizing antibody directed against HA, or even neuraminidase, the other major surface glycoprotein of influenza viruses. Like the HAI titers, the VNA titers against A/California/07/2009 (H1N1) increased following vaccination (p<0.001) and correlated significantly with protection (ROC area 0.80, p<0.05). This is not surprising, considering that the antibodies targeting the head domain of HA (and thus capable of mediating HAI) are a major part of the total virus-neutralizing antibody response [26], [27]. Interestingly, neutralizing antibodies against more conserved epitopes were also present, as indicated by the fact that neutralizing titers against A/Hong Kong/156/97 (H5N1) virus were detectable in most serum samples (Fig. 4C). Although these titers slightly increased after vaccination (p<0.001), the correlation between these VNA titers and survival following H5N1 challenge was not statistically significant.


Transient humoral protection against H5N1 challenge after seasonal influenza vaccination of humans.

Roozendaal R, Tolboom J, Roos A, Riahi S, Theeuwsen J, Bujny MV, Klaren V, Korse HJ, Dekking L, Grootenhuis A, Weverling GJ, Koudstaal W, Goudsmit J, Radošević K - PLoS ONE (2014)

Serum VNA titers correlate with protection against H1N1 but not H5N1 challenge.VNA titers against (A) A/California/07/2009 (H1N1) and (C) A/Hong Kong/156/97 (H5N1) were determined. Titers for mice that survive challenge (open squares) and mice that succumb to infection (closed squares) are presented separately for pre-vaccination (pre) and post-vaccination (post) sera. Assay background level is indicated with dashed line in panels A and C. Vaccine homologous H1 VNA titers are higher in post-vaccination serum (p<0.001, t-test). H5 VNA titers are detectable in some pre-vaccination samples and are higher in post-vaccination serum (p<0.001, t-test). ROC curves were calculated to assess the correlation (B) between H1N1 A/California/07/2009 VNA and protection against H1N1 A/Netherlands/602/2009 challenge and (D) between H5N1 A/Hong Kong/156/97 VNA and protection against H5N1 A/Hong Kong/156/97 challenge. H1N1 VNA correlates with protection against homologous H1N1 challenge (ROC area = 0.80, p<0.05, 95% CI 0.66–0.94). The positive correlation between H5 VNA and H5 protection does not reach statistical significance (ROC area = 0.66, 95% CI = 0.496–0.82).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4116209&req=5

pone-0103550-g004: Serum VNA titers correlate with protection against H1N1 but not H5N1 challenge.VNA titers against (A) A/California/07/2009 (H1N1) and (C) A/Hong Kong/156/97 (H5N1) were determined. Titers for mice that survive challenge (open squares) and mice that succumb to infection (closed squares) are presented separately for pre-vaccination (pre) and post-vaccination (post) sera. Assay background level is indicated with dashed line in panels A and C. Vaccine homologous H1 VNA titers are higher in post-vaccination serum (p<0.001, t-test). H5 VNA titers are detectable in some pre-vaccination samples and are higher in post-vaccination serum (p<0.001, t-test). ROC curves were calculated to assess the correlation (B) between H1N1 A/California/07/2009 VNA and protection against H1N1 A/Netherlands/602/2009 challenge and (D) between H5N1 A/Hong Kong/156/97 VNA and protection against H5N1 A/Hong Kong/156/97 challenge. H1N1 VNA correlates with protection against homologous H1N1 challenge (ROC area = 0.80, p<0.05, 95% CI 0.66–0.94). The positive correlation between H5 VNA and H5 protection does not reach statistical significance (ROC area = 0.66, 95% CI = 0.496–0.82).
Mentions: Therefore, we also determined the neutralizing activity of the serum samples against A/California/07/2009 (H1N1) and A/Hong Kong/156/97 (H5N1) viruses using a virus neutralization assay (VNA) (Fig. 4). In contrast to the HAI assay, the VNA assay is not selectively sensitive for the activity of antibodies that target the head region of HA, but is also able to detect the activity of any neutralizing antibody directed against HA, or even neuraminidase, the other major surface glycoprotein of influenza viruses. Like the HAI titers, the VNA titers against A/California/07/2009 (H1N1) increased following vaccination (p<0.001) and correlated significantly with protection (ROC area 0.80, p<0.05). This is not surprising, considering that the antibodies targeting the head domain of HA (and thus capable of mediating HAI) are a major part of the total virus-neutralizing antibody response [26], [27]. Interestingly, neutralizing antibodies against more conserved epitopes were also present, as indicated by the fact that neutralizing titers against A/Hong Kong/156/97 (H5N1) virus were detectable in most serum samples (Fig. 4C). Although these titers slightly increased after vaccination (p<0.001), the correlation between these VNA titers and survival following H5N1 challenge was not statistically significant.

Bottom Line: This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays.Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations.In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.

View Article: PubMed Central - PubMed

Affiliation: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Crucell Holland BV, Leiden, the Netherlands.

ABSTRACT
Current influenza vaccines are believed to confer protection against a narrow range of virus strains. The identification of broadly influenza neutralizing antibodies (bnAbs) has triggered efforts to develop vaccines providing 'universal' protection against influenza. Several bnAbs were isolated from humans recently vaccinated with conventional influenza vaccines, suggesting that such vaccines could, in principle, be broadly protective. Assessing the breadth-of-protection conferred to humans by influenza vaccines is hampered by the lack of in vitro correlates for broad protection. We designed and employed a novel human-to-mouse serum transfer and challenge model to analyze protective responses in serum samples from clinical trial subjects. One dose of seasonal vaccine induces humoral protection not only against vaccine-homologous H1N1 challenge, but also against H5N1 challenge. This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays. Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations. Strategies to increase the breadth and duration of the protective response against influenza are required to obtain 'universal' protection against influenza by vaccination. In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.

Show MeSH
Related in: MedlinePlus