Lessons learned from recent randomized controlled trials comparing the immunogenicity of different infant vaccination schedules of pneumococcal conjugate vaccine

Spijkerman et al. (2013)

Using a cohort of 400 healthy, term, Dutch infants, Spijkerman et al.³ conducted a large randomized control trial to test the immunogenicity of four different dosing schedules. In this study, infants were randomized (1:1:1:1) to receive three doses of PCV13 either at 2, 4, and 6 months (regimen 1); 2, 3 and 4 months (regimen 2); or to receive just 2 doses of PCV13 at 3 and 5 months (regimen 3) or at 2 and 4 months (regimen 4). Every group received a booster dose at age 11.5 months. To compare differences in immunogenicity across these four schedules, they used observed immunoglobin G (IgG) concentration values (GMC in μg/mL) one month after the primary series and one month after the booster dose.

Upon observation one month post primary series, IgG GMCs for the 2-4-6 schedule were higher for three serotypes than the 2-3-4 and 3-5 schedules. The 3-5 schedule was superior to the 2-4-6 and 2-3-4 schedules for one serotype and the 2-3-4 schedule was higher than the 2-4 schedule for 5 serotypes (Figure 1).

Figure 1. IgG geometric mean concentrations one-month post-primary series.

However, these high-level comparisons, in which the statistics sought to measure superiority of one schedule compared to all other schedules, may have significantly understated the observed differences in immunogenicity. When assessing this instead as pairwise comparisons by serotype across schedules, the differences in immune responses to the primary series were more striking. Unsurprisingly, 2-4-6 was statistically superior to 2-4 for 11/13 serotypes. Yet it was surprising that 2-4-6 was superior to 3-5 only for 4/13 serotypes (Table 2). The former is an intuitive finding, but the latter is somewhat surprising and quite interesting: delaying the onset of the primary series (as observed in the 3-5 dosing schedule) seemed to yield better immune responses despite the omission of one of the priming doses (as observed in the 2-4-6 and 2-3-4 schedules). This argues that the timing of doses may be more relevant than the total number of doses in the priming series.

Emphasizing this same point, while also testing the question of dose spacing, the 2-4-6 schedule outcompeted 2-3-4 for 10/13 serotypes, indicating that the increased spacing between priming doses (2 months apart instead of 1) elicited significantly better immune responses. Delayed onset of dosing also appeared immunologically superior given that the 3-5 schedule yielded significantly higher GMCs than the 2-4 schedule for 11/13 serotypes. A surprising and counterintuitive finding was that two doses at 3-5 months yielded superior GMCs than did three doses at 2-3-4 months for 5/13 serotypes. This further demonstrates that the total number of doses given may be less important than the age of the child at the time of vaccine administration.

They also assessed persistence of immune responses following each schedule, testing GMCs again at 8 months (Figure 2) and before the booster dose at 11.5 months (Figure 3). Overall, the 2-4-6 schedule had better persistence at eight months, followed by the 3-5 schedule and both schedules were superior to the 2-4 and 2-3-4. These observations suggest that delaying the onset of doses coupled with the longer intervals between doses yield higher immune responses than dosing schedules where doses are administered earlier in life and closely together. If the goal of dosing schedules is to provide protection early in life, then the 2-4-6 or 3-5 schedules appear to be the most desirable of the four regimens. If we are thinking about this in terms of cost comparisons of these schedules in relation to the total number of doses given, the 3-5 schedule delivers comparable immune responses to the 2-4-6 schedule at a lower price. While the immune responses across all four regimes wane pre-booster, the 2-4-6 and the 3-5 schedules continue to offer the highest residual GMCs.

Figure 2. IgG geometric mean concentrations at 8 months.

Figure 3. IgG geometric mean concentrations pre-booster.

Despite these differences in post primary and pre-boost GMCs, the immune responses following a booster at 11.5 months resulted in significant increases in GMCs, with little variation based on primary schedule (Figure 4). Here, the booster dose acts as the great equalizer between dosing schedules and emphasizes its importance for achieving high immune responses.

Figure 4. IgG geometric mean concentrations one-month post-booster.

In summary, this simple yet elegant experiment yielded a wealth of important and in some cases surprising findings.

First, the absolute number of doses given appeared to be less important than when doses were given. Delaying the onset of PCV administration until later in life (3 months instead of 2 months) may not be a prudent decision for settings that have not reached herd immunity since it leaves infants vulnerable to pneumococcus infection longer. However, in settings with established herd immunity, this herd immunity should provide critical, indirect protection to these infants and allow for flexibility. In these settings, moving the onset of dosing schedules to later in life may not add any undue risk to the infant.

Second, a larger spacing between doses (2 months apart vs. 1 month apart) appeared particularly important, as demonstrated by the fact that 3-5 and 2-4 generally outperformed the 2-3-4- schedule.

Lastly, the booster dose acted as the great equalizer, such that the IgG GMCs were essentially indistinguishable regardless of which priming series had been used.

Also notable was that serotype 3 appeared far less immunogenic than the others, a finding that has been noted elsewhere. Each of these findings has obvious practical implications, as will be discussed subsequently.

Goldblatt et al., (2018)

Five years later in the UK, Goldblatt et al.⁴ conducted a similar study to observe how changing the number of priming doses in the PCV dosing schedules would impact serotype-specific IgG GMCs. Unlike the United States, which launched PCV7 using a 2-4-6 priming schedule with a booster at 12 months, the UK instead chose a 2+1 schedule (two priming doses plus a booster in the second year) based on earlier field immunogenicity studies suggesting that this approach would be effective. In the current study, Goldblatt pushed this concept to the next logical point, testing whether a further reduction in priming doses to a 1+1 schedule would be feasible and comparable to the current standard of care. Here, infants were randomized (1:1) to two different dosing schedules, a 2+1 dosing schedule (current standard of care) and an experimental 1+1 dosing schedule. In the 2+1 schedule, infants received two priming doses at 2 and 4 months with a booster dose at 12 months and in the 1+1 schedule, infants received a single priming dose at 3 months and a booster dose at 12 months.

As shown in Figure 5, consistent with expectations, the 2-4 schedule yielded higher GMCs than a single dose at 3 months for 12/13 serotypes. Yet, similar to what was observed in the experiment by Spijkerman et al.³, following the boost at 12 months, GMCs were quite similar between the two schedules, with observed GMC ratios close to 1.0 for most serotypes. Interestingly, while the 2-4 schedule had yielded statistically significantly higher post boost GMC ratios for 4/13 serotypes, a single dose at 3 months yielded significantly superior GMC ratios for 4 of the serotypes. In other words, neither schedule offered a clear advantage over the other. The lack of a clear difference between infants regardless of whether they received one or two priming doses, suggests that a 1+1 dosing schedule could be a less costly but similarly effective alternative to the 2+1 dosing schedule, provided that this is done in a setting where high levels of herd immunity had already been achieved. This finding has obvious practical implications.

Figure 5. Observed differences in IgG geometric mean concentrations one-month post-primary and post-booster.

Moreover, when considering the post boost responses in terms of the proportion of infants achieving 0.35 μG of serotype specific IgG (the putative, though somewhat controversial, threshold for protection), 100% of participants were seroprotected against 12/13 serotypes^6–8. The exception was again serotype 3, where only 75.9% and 78.8% of the infants randomized to the 2–4 month and 3 month priming schedules, respectively, met or exceeded that threshold.

Kandasamy et al. (2019)

The studies conducted by Spijkerman et al.³ and Goldblatt et al.⁴ were both conducted in high-income/low disease burden settings. It is safe to assume that these same issues in terms of dose timing, spacing, and dose number would be at least as important, if not more, in low-income/high disease burden settings. Accordingly, Kandasamy et al.⁵ conducted a PCV dose schedule study amongst a cohort of Nepalese infants to compare two different dosing schedules, this time using the PCV10 vaccine. Working within the WHO’s EPI schedule of 6-10-14 weeks, infants were randomized (1:1) to receive two priming doses of PCV10 at 6 and 10 weeks (6–10) or at 6 and 14 weeks (6–14), with both groups receiving a booster dose at 9 months of age to complete a 2+1 schedule. The rationale for moving the boost earlier in life to 12 months was to take advantage of the scheduled administration of the measles vaccine at that age, without which a fifth vaccination visit would have to have been created de novo.

To note, the post primary responses for the 6–10 and 6–14 groups were both assessed at 18 weeks. Theoretically, this strategy could penalize the 6-10 regimen to some degree, since it introduces another month for initial antibody concentrations to wane.

With that caveat, as shown in Figure 6, the post primary responses were quite similar between the 6–10 and 6–14 groups, though in general, the 6-14 group GMCs trended higher for most serotypes. These differences were less obvious when reassessed at 9 months, just prior to the boost dose, basically because GMCs had fallen to baseline for most serotypes. However, one month after the 9-month boost, there were robust immune responses to all serogroups (Figure 7). The GMCs were nearly identical for all PCV10 serotypes, irrespective of priming schedule. As seen in the papers by Spijkerman et al.³ and Goldblatt et al.⁴, once again, the booster dose acted as a grand equalizer, largely erasing the subtle differences following different priming series.

Figure 6. IgG geometric mean concentrations of Nepalese infants one-month post second priming dose.

Figure 7. IgG geometric mean concentrations of Nepalese infants one-month post booster dose.

Some exceptions were observed: post-booster GMCs for serotypes 18C and 19F were somewhat higher among infants who received doses at 6-14 than for 6-10. And again, serotype 3 was an immunological dud compared with all other serotypes. Apparently, the comparative underperformance of serotype 3 is not limited to PCV13, but also occurs with other PCV formulations, arguing that the technical construction of the vaccine seems less likely at fault¹³. Rather, there may be intrinsic limitations in how the immune system engages serotype 3 antigens specifically¹⁴.