Injectable rotavirus vaccines—what value could they bring?

Currently available live, oral rotavirus vaccines (LORVs) are reducing severe diarrhea everywhere they’ve been introduced, but they are not as effective in the places with the highest burdens. Additionally, fewer than half of middle-income countries have introduced rotavirus vaccines (at least in part, because they do not qualify for financial support from Gavi, the Vaccine Alliance). Next-generation rotavirus vaccine approaches currently in late-stage clinical development may address barriers to vaccine uptake and access.

Injectable next-generation rotavirus vaccine (iNGRV) candidates are expected to provide superior efficacy in high-burden settings compared to current LORVs. This is because they bypass the child’s gut, which scientists think is responsible for the lower efficacy seen with the oral options. The most advanced iNGRV is the trivalent P2-VP8 candidate, which PATH is currently evaluating in a Phase 3 study in Ghana, Malawi, and Zambia. Because iNGRVs are injected, they also could potentially be combined with other injectable vaccines in the childhood immunization schedule.

Oral next-generation rotavirus vaccines (oNGRVs)—which include a dose administered at birth followed by two infant doses—offer yet another approach. Preliminary evidence from one such candidate has shown higher efficacy than current LORVs in clinical trials.

“It’s important to understand which of these potential advantages—higher efficacy, lower cost, more convenient administration—are the key drivers of stakeholder decision-making, and value propositions can give us those insights,” says William (Bill) Hausdorff, PhD, Lead, Public Health Value Propositions for PATH’s Center for Vaccine Innovation and Access (CVIA). To answer these questions, PATH conducted a series of studies and analyses to better understand the full public health value of iNGRVs.

“We know from previous experience that sometimes demonstration of clinical efficacy against a priority disease is not enough to guarantee sufficient commercial interest to bring a vaccine candidate to licensure or to stimulate country demand,” continues Bill. “The ultimate goal is to develop vaccines that are widely used because vaccination is the only way they will actually protect people from disease.”

To help guide this work, PATH conducted two targeted analyses. The first was to better define the target age group—some have proposed focusing on young infants, and others have suggested that an iNGRV could serve as a booster to children already vaccinated with the current LORVs. The second was to identify potential future combination options for iNGRVs.

After a careful look at the epidemiological literature, PATH’s analysis suggested that the incremental value of a booster dose would be marginal, in large part because most severe rotavirus disease occurs before a booster dose would be given at 9 or 12 months of age. Given this, PATH focused its value proposition efforts on understanding how iNGRV delivered to young infants can improve protection at a very early age.

The second analysis, which PATH conducted with the firm Linksbridge, aimed to identify which injectable infant vaccine, in theory, would make the most sense to combine with iNGRV in the future. The market assessment determined that iNGRV combinations with DTP-pentavalent (a vaccine that prevents five diseases— diphtheria, tetanus, pertussis, Haemophilus influenzae type B, hepatitis B) and DTP-hexavalent vaccines (a vaccine that prevents six diseases, the same as in DTP-pentavalent and polio) are the most promising to explore in the future due to their widespread use and expected substantial market shares through 2030.

The heart of PATH’s iNGRV value proposition comprised three key components:

1. Understanding the health impact and cost-effectiveness of iNGRVs.
2. Gathering the perceptions of national stakeholders and health care practitioners of iNGRVs.
3. Translating the latter analysis into a projected vaccine demand forecast.

In each analysis, we compared various hypothetical use cases of iNGRV in young infants—moderate or high efficacy, stand-alone or combined with a DTP-containing vaccine—with LORVs and oNGRVs.

The expected cost and impact of a given vaccine are two factors that stakeholders typically examine when making vaccine introduction decisions. PATH conducted a modeling study to assess the potential impact and cost-effectiveness of different rotavirus vaccine strategies in 137 low- and middle-income countries (LMICs).

The results predict that an iNGRV with higher efficacy compared to current LORVs would prevent an additional 200,000 rotavirus deaths over ten years and that vaccination programs with an iNGRV would save billions of dollars compared to current LORV vaccination programs over the same time frame.

Terms in image below: ROTAVAC®, ROTASIIL®, and ROTARIX® are currently available live, oral rotavirus vaccines. Abbreviations: iNGRV-DTP, injectable next-generation rotavirus vaccine combined with a diphtheria-tetanus-pertussis-containing vaccine; oNGRV, oral next-generation rotavirus vaccine.

Additionally, this study found that an iNGRV with comparable or superior efficacy to current LORVs is likely to be cost-effective in the majority of LMICs. Most strikingly, an iNGRV-DTP combination vaccine is likely cost-effective in all LMICs and is cost-saving in many.

“One of the interesting things about this analysis is the cost-effectiveness of a stand-alone iNGRV or iNGRV-DTP combination vaccine,” says Fred Debellut, Senior Health Economist with CVIA. “These use cases are highly cost-effective in low- and middle-income countries even if iNGRVs end up having efficacy levels similar to current LORVs.”

Local stakeholders are the ultimate decision-makers. They choose whether or not to introduce new vaccines into their country’s immunization schedule. Yet, vaccine developers generally do not take their perspectives into account when designing candidate vaccines.

PATH led a feasibility and acceptability study in six countries to understand local stakeholder preferences for different attributes of hypothetical NGRV products. Interviews were conducted with 71 national stakeholders who make vaccine decisions and 64 health care providers who administer vaccines in Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka. These stakeholders and providers were asked to indicate their preferences for different rotavirus vaccine options and explain the reasons for their choices.

“The childhood immunization schedule is getting more and more crowded as new vaccines are developed and introduced,” says John Tanko Bawa, Vaccine Implementation Team Lead for Africa with CVIA and the study investigator for Ghana. “It’s important to understand country-level preferences for new vaccines earlier in the development process so that you end up with a vaccine that meets country needs that they can—and want to—incorporate into their vaccination programs.”

Results from the study indicate that vaccine delivery considerations were the most important preference drivers for national stakeholders, followed by improved efficacy and cost. Nearly half preferred a higher efficacy, stand-alone iNGRV over existing LORVs despite reservations about adding new injections to the vaccination schedule. Most strikingly, a vaccine that combined an iNGRV with a DTP-containing vaccine into one formulation was by far the most preferred approach among national stakeholders over all oral options, including a high-efficacy oNGRV, due to the ease of delivery and lower cost.

Almost all health care providers strongly opposed adding an injectable rotavirus vaccine to the vaccination schedule. However, because the study wanted to focus on delivery concerns, health care providers were not given efficacy or cost information about the vaccine options, so it’s unclear if a higher efficacy iNGRV would impact this preference. In contrast, they were quite supportive of iNGRV if it was combined with a DTP-containing vaccine.

Taken together, these results help elucidate under what circumstances and use cases iNGRVs would offer a compelling public health value proposition. The potential impact, cost-effectiveness, and national stakeholder interest in iNGRVs are markedly dependent on the product profile. While an iNGRV with high clinical efficacy is clearly most desirable, these results also suggest that an iNGRV with efficacy similar to LORVs could be a strongly preferred option if combined with a DTP-containing combination vaccine.

These findings may help to target donor and vaccine development investments toward the most preferred and cost-effective formulations of iNGRVs. They also highlight the importance of structured consultations with a variety of country stakeholders about vaccine preferences.

“Global and national rotavirus vaccine policy recommendations, as well as Gavi’s strategic planning efforts should be informed by these strong country preferences for alternatives to the currently available LORVs,” says Bill. “In addition, they should consider the estimated higher health impact and enhanced cost-effectiveness of most iNGRV candidates and the significant interest across a variety of stakeholders in the integration of rotavirus protection into DTP-containing combination vaccines.”