A data collection template was designed for all vaccines in clinical development according to the PATH respiratory syncytial virus (RSV) vaccine and monoclonal antibody (mAb) Snapshot, updated November, 2017 (appendix). Vaccines were divided into four major groups: particle-based, vector-based, live-attenuated or chimeric, and subunit vaccines. Immunoprophylaxis with mAbs was included as a fifth category. Gaps in knowledge were identified through a search of PubMed for clinical trials with
ReviewThe respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates
Introduction
Acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV) has gained recognition as a global health problem with a high burden of disease, and no vaccine licensed for prevention. In children under 5 years, it is estimated that 33·1 million episodes of ALRI, 3·2 million hospital admissions, and as many as 118 200 deaths were attributable to RSV worldwide in 2015 (figure 1).1 Although often characterised as a paediatric disease, RSV infection in adults represents a substantial health burden. Mortality attributable to RSV in adults aged 65 years or older is estimated to be 7·2 per 100 000 person-years,7 and 8% of RSV ARLI among older adults admitted to hospital was reported to result in death8 in the USA. RSV vaccine candidates aim to protect at least three target populations that are at risk for severe RSV disease: (1) young infants (0–6 months), (2) older infants and young children (2 months or older) through active immunisation, and (3) older adults (65 years or older).
Development of effective RSV vaccines and monoclonal antibodies (mAbs) presents both opportunities and challenges. First, concerns of enhanced respiratory disease (ERD) following vaccination with the formalin-inactivated RSV (FI-RSV) vaccine in the 1960s have complicated the design and testing of RSV vaccines.9 Second, an absolute correlate of protection against a clinically relevant RSV infection remains elusive, although cell-mediated immunity,10 mucosal IgA,11 and potent neutralising antibodies12 have been associated with decreased disease severity.
Between 2016, and 2017, three phase 2b or phase 3 trials (two vaccine trials in older adults13, 14 and one mAb trial in infants15) did not meet clinical endpoints. In addition to possible inadequacies in trial design and implementation, the failure of these candidates shows the continued gaps in knowledge regarding immunological mechanisms of protection in the different target populations. Another challenge to RSV vaccine design is the lack of consensus regarding clinical endpoints, which might differ according to the target population. Finally, a consideration in RSV vaccine development is the limited protection conferred by immune responses elicited by natural RSV infection. Natural immunity provides only transient protection against subsequent infection, and re-infection occurs frequently,16 although the most severe RSV disease is usually observed during the primary infection. mAbs circumvent the problem of transient immunity to RSV and an immature immune response to vaccination in young infants at risk of severe disease. An ideal RSV vaccine candidate should prevent severe disease in at-risk populations and might also lessen person-to-person transmission.17
Despite these obstacles, there are several opportunities for RSV vaccine and mAb development. First, RSV disease burden has received increasing attention from international stakeholders such as WHO18 and the Bill & Melinda Gates Foundation, based on better estimates of RSV-associated mortality worldwide.19 Second, the discovery and stabilisation of the prefusion (pre-F) conformation of the RSV surface fusion (F) glycoprotein provided a new target for vaccines and mAbs20, 21 as pre-F specific antibodies might be more potent than postfusion (post-F) antibodies in protecting against RSV ALRI. Third, pharmaceutical companies have recognised the urgent unmet need of RSV prevention and prioritised the development of RSV vaccines and mAbs.
In 2015, RSV prevention and therapeutic strategies were reviewed, identifying ten vaccines in clinical development.22 An update of the 2015 review is necessary in light of the recent failures and new candidates in the years since 2015. In this Review, we show that only 40% (four of ten) of the vaccine candidates from 2015 are continuing in clinical trials and 14 additional new vaccine candidates have entered clinical trials (figure 2). A single vaccine candidate can be in clinical development both in different populations and in different clinical phases; in these instances, they are considered to be additional candidates. Therefore, the RSV F nanoparticle is considered to be three candidates and Ad26.RSV.preF to be two. Throughout the manuscript we have adhered to the 19 vaccine candidates and mAbs in clinical development according to the PATH Vaccine Snapshot.23
Section snippets
RSV vaccine history
RSV vaccine development started shortly after the first identification of the virus in humans in 1957.24 However, ERD upon natural RSV infection after vaccination with a FI-RSV candidate in a series of trials in the 1960s severely hindered inactivated virus and subunit vaccine development for many years. Nevertheless, work continued on the development and human testing of live-attenuated RSV vaccine candidates. In the following 60 years, only two products were licensed for prevention of RSV:
Lessons from the vaccine and mAb graveyard
There have been three late-phase vaccine and mAb trial failures between 2016, and 2017 (table 1). It is important to distil lessons learned from these results to inform future vaccine development. First, a phase 3 trial in 1149 healthy preterm infants was done to evaluate REGN2222 (suptavumab), a mAb against antigenic site V on the RSV pre-F protein.25 The trial did not meet its primary efficacy endpoint to prevent medically attended RSV infections up until day 150 of life.26 REGN2222 was
Vaccine antigens
Vaccine antigens included in RSV vaccine candidates are diverse. The majority of vaccines in clinical trials (11 of 18) use the F protein, a class I viral fusion protein, as an antigenic target. The RSV F protein is highly conserved and facilitates viral fusion with host cells. Understanding the structural differences between pre-F and post-F conformations, and stabilisation of the pre-F soluble forms, has resulted in advances in vaccine antigen design.21, 34 Current vaccine candidates use
Target populations
RSV prophylactic interventions are designed to protect at least two populations most susceptible to severe RSV disease: RSV-naive young infants and children, and older adults, although other high-risk populations are important to consider. It is estimated that 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in infants younger than 6 months of age,1 an age at which vaccines are generally less immunogenic. Older adults and adults with chronic cardiopulmonary conditions
Immunological endpoints
Antibodies are thought to be the key players in limiting RSV ALRI as evidenced by proven protection in immunoprophylaxis trials in children.50, 51, 52 Evidence from experimental human infection in adults suggests a protective role for nasal RSV-specific IgA against RSV infection,11 underscoring the importance of mucosal immunity. A limited ability to generate memory IgA responses after RSV infection could be in-part responsible for incomplete immunity and subsequent RSV re-infection. Antibodies
Vaccine strategies
We have divided vaccines in clinical development into four categories in accordance with the PATH RSV vaccine and mAb snapshot: particle-based, vector-based, subunit, and live-attenuated or chimeric vaccines.24 We have also included mAbs in clinical development for the prevention of RSV ALRI. In the snapshot there are 43 vaccines and four mAbs in development, of which 19 are in clinical stage development. In table 4 we provide a comprehensive overview and more detailed comparison of all
Considerations by regulatory agencies and WHO
Considerations in population selection for vaccine trials mentioned by the European Medicines Agency (EMA) include: first testing a vaccine candidate in a seropositive before testing in a seronegative population, testing a maternal vaccine in non-pregnant women of child-bearing age before testing in pregnant women, and including older adults with comorbidities in vaccine trials. No particular considerations were mentioned for population selection in studies for mAbs. In October, 2017, the EMA
Discussion
Challenges in RSV vaccine design include concerns of ERD post-vaccination, lack of definitive immunological correlates of protection, lack of consensus regarding clinical endpoints, and little natural immunity following RSV infection. Despite these challenges, developments such as an understanding of the structural biology of the RSV fusion protein, as well as lessons learned from late-phase vaccine trial failures have informed the field as it moves forward.
We attempted to collect data
Search strategy and selection criteria
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Dr Melero died in March, 2018