No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines

Abstract

Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted with alum or the TLR4 agonist monophosphoryl lipid A can be used to advance understanding of the relationship between vaccine side effects and immunization outcomes.

Conflict of interest statement

Conflict of interest

None declared.

Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

The main reasons parents refused HPV immunization for their teen-aged children. About 20% of parents who responded to the National Immunization Survey – Teens 2008–2010 (N ~ 33 000/year) had refused HPV immunizations for their teen-age daughters and cited one of the indicated statements as ‘the main reason’ for their decision. Error bars denoting 95% confidence intervals are shown only for ‘safety concern/side effects’ and ‘not needed/not necessary’ for clarity. Data from Darden et al. (2013) [6].

Figure 2

Humoral responses to vaccines adjuvanted with alum + MPL versus alum alone. Serum titers from three clinical studies performed as double-blind, randomized head-to-head comparisons of vaccines are shown; N is for according-to-protocol. (a) Cervarix versus Gardasil in seronegative girls age 9–14, N = 187 according-to-protocol (ATP). Study participants were immunized twice at 0 and 6 months and serum titers of HPV-18 neutralizing antibody were measured from 7 through 36 months; data from [54,55]. (b) Cervarix versus Gardasil in seronegative women age 18–26, N = 248 ATP. Participants were immunized thrice at 0, 1–2 and 6 months and serum titers of HPV-18 neutralizing antibody were measured from 6 through 60 months; data from one of three age-stratified groups reported in [–53]. (c) Fendrix versus Engerix-B in seronegative women and men age 18–45, N = 104 ATP. Participants were immunized on days 0, 30 and 360 and serum titers of HBsAg-specific antibody were measured from 30 to 390 days; data from [56•,57]. N values are for participants who completed each study according-to-protocol. (All) Black arrows: vaccine immunizations in each study. Bold lines: geometric mean titers of serum antibodies. Thin lines: upper and lower confidence intervals (95%). Dotted lines: neutralizing Ab titer of women who had cleared natural HPV infection (a, b) or HBsAg-specific titer associated with immunity to HBV (c).

Figure 3

Inflammatory side effects of vaccines adjuvanted with alum + MPL or alum. The percentages of participants who experienced general or local adverse events after vaccine dose 1 in the clinical studies described in Figure 2 are shown. Blue and red bars: instances of adverse events after intramuscular injection of vaccines containing alum + MPL (Cervarix and Fendrix) or alum alone (Gardasil and Engerix-B), respectively. Instances of arthralgia were not recorded after administration of Fendrix or Engerix-B. For each cluster shown, bars from top-to-bottom correspond to adverse events after injection of Cervarix versus Gardasil in N = 716 girls age 9–14 from France, Hong Kong, Singapore and Sweden; Cervarix versus Gardasil in N = 249 women age 18–26 from the US; and Fendrix versus Engerix-B in N = 282 adult women and men age 18–45 from Belgium and Germany. Data from [53,55,57]; N indicates all participants enrolled in each study who received vaccine dose 1 regardless of pre-immune status or completion of the immunization series according-to-protocol.