Chapter 2
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Glycoconjugate Vaccines: The Clinical Journey Stephen P. Lockhart,*,1 Daniel A. Scott,2 Kathrin U. Jansen,3 Annaliesa S. Anderson,3 and William C. Gruber3 1Pfizer
Vaccines Clinical Research and Development, Horizon Building, Honey Lane, Hurley SL6 6RJ, United Kingdom 2Pfizer Vaccine Clinical Research and Development, 500 Arcola Rd., Collegeville, Pennsylvania 19426, United States 3Pfizer Vaccines Research and Development, 401 N. Middletown Rd., Pearl River, New York 10965-1299, United States *E-mail:
[email protected].
We review the clinical journey of glyconjugate vaccines from their inception in the 1980s to contemporary vaccines and their positive public health impact. We focus on novel and ground breaking clinical trials, particularly those leading to marketing approvals for new categories of vaccines. Glyconjugate vaccines based on capsular polysaccharides have been highly successful against Haemophilus influenzae type b, a growing number of Streptococcus pneumoniae serotypes and Neisseria meningitidis serogroups A, C, W and Y. Glycoconjugate vaccines may extend this success to other encapsulated bacteria such as Salmonella typhi, Group B Streptococcus and Staphylococcus aureus as well as Shigella and Escherichia coli.
© 2018 American Chemical Society Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
Introduction Many important human bacterial pathogens are carried as colonizing organisms and only occasionally become pathogens. These pathogens have a polysaccharide capsule which is a key element in the close relationship between them and the host. The capsule paradoxically protects the organisms and yet also presents a key target for antibody-mediated host defense. On the basis of experiments started in the 1920s (1), the potential of Streptococcus pneumoniae (also known as pneumococcus) capsular polysaccharide conjugates to induce protective immune responses in animal models was identified nearly 80 years ago (2). A number of bacterial vaccines based on plain, unconjugated capsular polysaccharides were developed in the second half of the twentieth century but limitations were noted, such as lack of immunogenicity in infants and failure to prime for immunological memory. It was not until the late 1970s that these shortcomings led to the development of capsular polysaccharide conjugate vaccines (3). Although each vaccine is unique, there have been some common steps in the clinical journey for conjugate vaccines, which will be illustrated with specific examples in this chapter. Of note, the development pathway for Haemophilus influenzae type b (Hib) conjugate vaccines set a strong precedent for all the following conjugate vaccines, particularly with regard to characterization of vaccine-induced protective immune responses using appropriate serological assays. Haemophilus influenzae invasive disease in infants and young children presented a good first target for Hib conjugate vaccines as a single serotype was responsible for almost all disease. Several generalizations can be made for polysaccharide conjugate vaccines: •
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Each type of conjugate vaccine currently marketed was preceded by plain polysaccharide (PS) vaccines. Plain PS vaccines induce protective antibodies through a T-cell independent mechanism, which induces very poor immune responses in infants, does not induce immune memory and often induces hyporesponsiveness to further vaccine doses. The early conjugate vaccines against some pathogens were approved on the basis of clinical efficacy studies, but vaccines for some pathogens and derivative vaccines were approved on the basis of immunological assessments based on experience with polysaccharide vaccine and only subsequently shown to be effective after implementation for widespread use. Immunological assessments for regulatory approval not only include achieving a concentration of antibody known or expected to be protective (also known as a correlate of protection), but also evidence of functional antibody being produced that kills the pathogen, induction of immune memory demonstrated by an enhanced response to a subsequent polysaccharide or conjugate vaccine dose challenge and evidence that the strength of antibody binding to its target (avidity) is enhanced. Development of standardized, sensitive, reproducible, high-throughput assays for measuring antibody responses to vaccines has been critical. 8 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
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In addition to direct protection of immunized subjects, reduced colonization produces “herd immunity,” which adds to protection of immunized subjects as well as unimmunized populations. Antimicrobial resistance (AMR) has been reduced by conjugate vaccines, due to reductions in carriage of potentially antibiotic resistant isolates and reductions in antibiotic use for treatment of common bacterial diseases, such as otitis media. Development of multicomponent vaccines or combinations with other vaccines has been important, though not always straightforward. Use in lower and middle income countries (LMIC) generally requires specific clinical trial evidence, tailored vaccine presentations such as multidose vials (MDV) and sometime specific vaccine combinations.
Notes: Except where specified, quoted efficacy is against first episode of an endpoint and calculated as intention to treat (ITT), primarily meaning that all subjects who received at least one dose are included from that dose onwards, whereas per protocol (PP) efficacy is generally calculated on first episodes occurring at least 2-4 weeks following completion of a full primary series of vaccination. The term efficacy is sometimes reserved for vaccine studies with randomly allocated treatment and control populations using an endpoint that combines a clinical and a microbiological component (e.g. Haemophilus influenzae (Hib) invasive disease). In this review we have also used the term efficacy where subjects are randomly allocated to a treatment or control treatment, but only a clinical endpoint can be ascertained (e.g. radiologically confirmed community acquired pneumonia (CAP)), which would sometimes be referred to as effectiveness trials. We have reserved the term effectiveness studies for observational studies where treatment is not randomly allocated. A range of numbers in parentheses following a point estimate in percent represents a 95% confidence interval, for example 5% (2, 17).
Haemophilus influenzae Type b (Hib) Early Clinical Experience with Polysaccharide Hib Vaccines Plain capsular polysaccharide vaccines for Hib, consisting of polyribosylribitol phosphate (PRP), were introduced in 1985 in USA for use in children 24 months to 6 years of age (4), based largely on clinical experience in Finland (5). Efficacy was limited to children over 18 months of age, whereas the peak of invasive disease was in younger infants (5). There was also inconsistency in measured effectiveness after introduction in the USA (6, 7). These issues were to an extent resolved by approval of the first Hib conjugate vaccine in 1985 (4). Serological Assays for Hib Vaccines The development of practical, sensitive and specific assays for human antibody responses to Hib vaccines was essential for clinical development of both 9 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
plain polysaccharide and conjugate Hib vaccines. These assays fall into two main groups, immunological assays for quantifying PRP-binding immunoglobulin or immunoglobulin classes, and functional assays such as serum bactericidal assays (SBA) that measure the actual killing of the pathogen. Consensus was that an immunological binding assay such as radioimmunosassay (RIA) (8) or enzyme-linked immunosorbent assay (ELISA) (9) was the primary method (10), as these are easier to perform, more reproducible, and more suitable for standardization (9). A functional assay such as an SBA is required to confirm that the binding antibodies are biologically active (11). Trials in Finland with the plain polysaccharide vaccine had suggested that Hib specific antibody concentrations of at least 1.0 µg/mL would be protective in older children (12).
Early Experience with Hib Conjugate Vaccines The first Hib conjugate constructs were published in 1980 (3), following work that had started in 1968 (13). By 1984 PRP-D (PRP conjugated to diphtheria toxoid (DT)) had been shown to be safe and more immunogenic than PRP in adults (14). In children 15-24 months of age PRP-D was more immunogenic than PRP (15) and on this basis was approved by FDA for use in children 18 months and older in 1987 (4). However, PRP-D efficacy studies in infants yielded conflicting results (Table 1), with good efficacy in Finnish infants (16) at 83% (26, 96) but no significant efficacy in Alaskan infants (17) at 35% (-57, 73). After three primary doses the Geometric Mean Concentration (GMC) was only 0.18 µg/mL in Alaskan infants, with only 48% achieving a concentration of 0.1 µg/mL (17). Even in the Finnish infants the GMC after three doses was only 0.42 µg/mL, with only 62% achieving a concentration of 0.15 µg/mL and 34% 1.0 µg/mL. PRP-D was approved and used in infants in Switzerland (18) but was never approved for use in infants in the USA, as other conjugate vaccines were soon shown to be more immunogenic and efficacious in infants. HbOC (Hib capsular oligosaccharide conjugated to CRM197 , a genetically detoxified diphtheria toxin) (19) and PRP-OMP (PRP conjugated to meningococcal outer membrane protein, a highly immunogenic protein extracted from serotype 2 Neisseria meningitidis) (20) entered clinical trials soon after PRP-D. A series of studies on HbOC allowed selection of an optimal process and conjugate design, and showed safety, immunogenicity and priming in adults and infants over 12 months of age (21), progressing to demonstration of immunogenicity with three doses in infants at 2, 4 and 6 months of age (22). Priming for immune memory was shown in infants using a PRP dose at 12 months of age (22). A similar series of studies with PRP-OMP also showed the vaccine to be safe in adults (23) before demonstrating safety and immunogenicity (23) and priming (24) in infants down to 2 months of age. PRP-OMP was immunogenic in infants and induced priming with two doses (23, 24). On the basis of immunogenicity being superior to that of the PRP vaccine in 24-26 month old children, HbOC was approved for use in toddlers in the USA in 1988 (4) and PRP-OMP a year later (4). 10 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
The induction of immune responses and priming in young infants led to efficacy studies in infants (Table 1). Excellent efficacy was shown in trials within the US for HbOC (25) and PRP-OMP (26). As a result, HbOC was the first conjugate vaccine approved for use in US in young infants, starting at 2 months of age, in 1990 (4), followed by PRP-OMP a few weeks later (4). PRP conjugated to tetanus toxoid (TT, PRP-T) was included in head-to-head immunogenicity studies comparing Hib conjugate vaccines in infants (27, 28). PRP-D was confirmed to be substantially less immunogenic than PRP-T, HbOC or PRP-OMP (28). After 3 doses these three vaccines were all similarly immunogenic (27). However, PRP-OMP showed an earlier response, with substantial immunogenicity after one dose, plateauing after two doses, whereas HbOC and PRP-T showed a substantial rise between 2 and 3 doses (14, 27, 28). The avidity of antibody after infant vaccination was, on the other hand, highest for HbOC, intermediate for PRP-T and lower for PRP-OMP (11). PRP-T was subsequently approved in the US on the basis of immunogenicity for US infants in 1993, after randomized efficacy studies were interrupted by the approval of Hib conjugate vaccines for infants (4). However, staged introduction in different areas prior to a national introduction in the UK confirmed that PRP-T was highly efficacious in infants (Table 1) (29). PRP-T was subsequently used in an efficacy trial in the Gambia (Table 1) (30). This trial confirmed that Hib was as efficacious in an LMIC setting as in a developed country. Excellent efficacy was shown against confirmed Hib pneumonia as well as all Hib invasive disease (30). The vaccine was efficacious against all radiological pneumonia (21.1%, 95% CI 4.6-34.9) (30). Defining the etiological agent responsible for pediatric pneumonia can be challenging as good quality sputum is very difficult to obtain and most children will not have a positive blood culture. This study therefore indicates in an indirect fashion that Hib was responsible for a substantial proportion of radiological pneumonia in infants in the Gambia (30). This study provided strong support for extending use of Hib vaccine to infants around the world. In Europe, the EMEA (European Medicines Evaluation Agency, now EMA) was not founded until 1995, so the regulatory roll-out of standalone Hib conjugate vaccines proceeded on a national basis in Europe. Nonetheless, deployment was rapid with substantial uptake in most of Western Europe and other developed countries (31).
11 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
Table 1. Haemophilus influenzae type b conjugate vaccine efficacy studies Abbreviation (Conjugate protein) First approved monovalent vaccine by proprietary name
First approval for use in infants in USA
Efficacy against invasive Hib disease % (95% CI)
Efficacy study schedule (months of age) Location
Efficacy study design
PRP-D (Diphtheria toxoid)
Only ≥18 months
83 (26, 96) (16)
3, 4, 6, 14 Finland
Treatment/ no treatment by date of birth
35 (-57, 73) (17)
2, 4, 6 Alaska
RDBPCT
1990
100 (64-100) (25)
2, 4, 6 Kaiser Permanente Northern California (KPNC)
Treatment/ no treatment by date of birth
1990
93 (53-98) (26)
1-3, 3-5a Navajo Reservation
RDBPCT
1993
100 (80-100) (29)
2, 3, 4 UK
Staged introduction by area
95 (67-100) (30)
2, 3, 4 Gambia
RDBPCT
ProHIBit®
HbOC (CRM197) HibTITER®
PRP-OMP (Meningococcal OMP) PedvaxHIB® PRP-T (Tetanus toxoid) ActHIB ®
a
2 doses at 42-90 days and 70-146 days, separated by at least 28 days. Randomized, double-blind, placebo-controlled trial.
RDBPCT:
Correlates of Protection for Hib Conjugate Vaccines A precise correlate of protection has been difficult to establish. After introduction of plain PRP vaccines ≥1.0 µg/mL was first used as a correlate of protection. However subsequently, with introduction of conjugate vaccines, a lower estimate of ≥0.15 µg/mL achieved within a month of completing a primary series or primary plus booster series of vaccination was used to assess response to conjugate vaccines in infants (32). The difference in these correlate values likely reflects qualitative differences between antibodies produced in response to plain polysaccharide vaccines rather than polysaccharide conjugate vaccine, such as differences in avidity maturation or development of immunological memory (32). Functional antibody titers determined in assays measuring complement mediated bactericidal killing were shown to correlate with binding antibody titers after Hib conjugate vaccine immunization (11). The WHO provides guidance on the clinical evaluation of Hib conjugate vaccines (10), which has been pivotal to 12 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
developing combination vaccines and to validating new manufacturing sites on the basis of immunogenicity. Key elements to be described include; •
• • • •
Percentage of subjects achieving Hib antibody concentrations ≥0.15 µg/ mL and ≥1.0 µg/mL one month after completion of a primary series and one month after a booster dose Functional activity of antibodies as assessed by serum bactericidal assays Persistence of antibodies to 4 years of age Immune priming demonstrated by a booster response (initially to plain PS vaccine but now usually to a dose of Hib conjugate) Immune priming demonstrated by avidity maturation
Protein Carrier-Mediated Immune Differences The question of the choice of carrier proteins in conjugate vaccines (e.g. CRM197, DT, TT, OMP or others) has been of interest from the very beginning of conjugate vaccine trials. It is possible that the response to the conjugate could be enhanced or reduced by the choice of carrier proteins. In addition, there is the possibility of enhancing or inhibiting the vaccine response in relation to other vaccines that are concomitantly given with the conjugate vaccine. The sequence of administration could also be relevant, demonstrated by the fact that administration of pediatric diphtheria and tetanus toxoid vaccines before and after conjugate vaccines did have disparate impacts (33). This topic has continued to be of interest as co-administration of and creation of combinations of vaccines has grown. For Hib conjugate vaccines the topic has been well reviewed (33, 34). In general, the standalone Hib conjugate vaccines had no clinically significant issues but there have been some interactions within combinations, particularly where multiple conjugates are combined, which will be touched upon below. Combination Vaccines The need for multiple injections poses a practical barrier to the introduction of new vaccines, particularly in infants and children. A logical next step was therefore the development of combinations including effective Hib conjugate vaccines with other primary infant vaccines. The first such vaccine combined HbOC with the components of a DTPw vaccine (diphtheria and tetanus toxoids with whole cell pertussis vaccine). In this combination the antibody responses to PRP, diphtheria toxoid and pertussis agglutinins were enhanced by the combination, although this was not necessarily of clinical significance (35). This DTPwHib combination was approved in US in 1993 as Tetramune® and was successfully marketed in a number of other countries. As whole-cell pertussis vaccine (Pw) has remained important in LMIC, pentavalent combinations of DTPw with Hib and hepatitis B vaccine (HepB) have been a cornerstone for improving Hib uptake in these areas (36). The first such pentavalent combination gained WHO prequalification in 2006 (37) and, following substantial effort to transfer Hib conjugate technology (38), there are 13 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
eight prequalified manufacturers, including companies in India and Indonesia as well as South Korea and Europe (37). In the 1990s a number of acellular pertussis vaccine (Pa) combinations were being developed for infants in wealthier countries and combinations of DTPa and Hib were soon developed. At least in part, this was in response to falling pertussis vaccine coverage due to public concerns about the safety and tolerability of whole-cell pertussis vaccines. Unfortunately, in 1996 a combined DTPa-PRP-T was found to produce lower Hib immune responses than PRP-T administered separately (39). Assessments of the quality of the immune response suggested that the response remained likely to be protective (40). Subsequently however, effectiveness of the Hib vaccine in the UK declined in children born around 2000, coinciding with a period when DTPa-Hib combinations were first used (41). It was noted that the UK was unusual in not including a Hib toddler booster dose (42). Use of a catch-up program in children up to 5 years of age followed by inclusion of a booster dose in the schedule led to resumed protection (42, 43), suggesting that sustained protection after a primary series with a conjugate vaccine cannot be assumed on the basis of an ability of infection to induce a memory response in individuals primed by conjugate vaccination; factors such as herd immunity due to reduced carriage in older subjects and sustained circulating antibody are also required. In more economically advantaged countries, Hib conjugate vaccines for infant doses and booster doses up to 5 years of age are now largely included in combinations of five (pentavalent) or six (hexavalent) pediatric vaccines, also including DTPa and inactivated polio vaccine (IPV) with or without hepatitis B vaccine (HepB). Two hexavalent combination vaccines were approved in the EU in 2000 (44, 45), although one was later withdrawn due to concerns about the level of HepB response (45), illustrating the difficulties of producing pediatric combination vaccines. Further hexavalent combinations are now approved in Europe and elsewhere (46, 47). No hexavalent combination has yet been approved by the FDA, although one pentavalent combination including a Hib vaccine is approved (48). Two additional types of combination Hib vaccines were developed. In 1996 the FDA approved a combined PRP-OMP and hepatitis B vaccine (COMVAX®) (49). Before DTPa vaccines were combined with HepB this allowed a reduction in the number of injections. However, with the development of larger combinations including hepatitis B and Hib vaccines this product was no longer required and was withdrawn in 2014. PRP-T has also been combined with meningococcal conjugate vaccines. A combined PRP-T and meningococcal group C conjugate vaccine (Menitorix®) is available in Europe and is used as a toddler dose in the UK routine schedule (50). A combined PRP-T, meningococcal group C and Y vaccine (Menhibrix®) was approved by the FDA in 2012, but was never recommended for routine use and has now been withdrawn by the manufacturer due to the resulting very limited demand (51).
14 Prasad; Carbohydrate-Based Vaccines: From Concept to Clinic ACS Symposium Series; American Chemical Society: Washington, DC, 2018.
Impact The impact of Hib vaccine was rapid and dramatic after its introduction in developed markets (31, 43). For example, by 1997 the number of reported Hib cases in children less than 5 years of age in USA had declined by 99%, making the disease a rarity even to hospital-based pediatric infectious disease specialists (52). In the UK, the incidence in children less than 5 years of age was over 20/100,000 before vaccination was introduced and fell below 1.0/100,000 within 3 years (41). In Finland similar dramatic impacts were noted, falling from 30 cases/year in the Helsinki area in 1986 when the program started to 0 cases in 1991 (53). The introduction of vaccine had a similar impact in LMIC such as the Gambia, where PRP-T was introduced as part of the Gambian expanded program on immunization (EPI) in May 1997, following extensive involvement in Hib efficacy trials in 1993-1996 (54). In Western Gambia where a surveillance program was conducted rates of invasive Hib disease fell from over 200/100,000 in children < 1 year of age in 1990-1993 to 0/100,000 by 2002 (54). However, continuing surveillance is critical as some reemergence of disease, albeit modest compared to the pre-vaccination incidence, was noted in UK (41) and Gambia (55). In the UK steps were taken to optimize schedules, as discussed above, leading to reversal of the resurgence (42, 43); by 2012-2016 the incidence across the whole population was
