Novel Immunotherapies Target RSV Disease at Both Ends of the Age Spectrum

Thanks to recent improvements in disease surveillance, it is now appreciated that respiratory syncytial virus (RSV) infections account for a significant share of U.S. hospitalizations for lower respiratory tract disease, importantly including bronchiolitis and pneumonia. And like seasonal influenza, very young children, the elderly and others with compromised immunity account for nearly all of the annual serious disease burden associated with RSV.

Yet while influenza is a household word, RSV remains relatively little known to the general public. Why this dichotomy? In part it’s because, each year, the general public is urged by providers and public health media campaigns to get immunized with a flu vaccine to prevent infection and illness. But at present, the converse is true for RSV: With the exception of one very narrowly indicated passive immunotherapy to protect very high-risk children,* there are no vaccines or other prophylactic immunotherapies to prevent serious RSV disease.

But with the anticipated approval of several highly promising RSV vaccines and passive prophylactic antibody therapies now in the development pipeline, RSV may transition from obscurity to broader public awareness as preventive treatment options become standard medical practice.

The U.S. RSV Disease Burden

Most children and adults infected during each typical five-month RSV season experience only minor cold-like upper respiratory symptoms, including rhinorrhea, coughing and sneezing, which generally resolve on their own within a week or two. However, infants in the first six months of life entering RSV season, premature infants born under 35 weeks of gestation, young children with congenital pulmonary or heart disease and adults over age 60 years with weakened immunity or chronic heart or lung disease are at much-increased risk of progressing to severe lower respiratory tract infection (LRTI).

Infants and at-risk young children. RSV is the most common cause of acute respiratory tract infections requiring medical intervention or hospital admission in infants and young children less than 2 years of age. While immaturity of immune defenses at this early age is clearly a contributor, another risk factor is a high surface-to-volume ratio of their still-developing airways. Because we are born with almost all of our airways and alveoli, the lumen size of bronchioles in infants is smaller relative to that of an adult and thus more prone to obstruction.¹ Not surprisingly, young children with a recent history of bronchopulmonary dysplasia are also at much increased risk of RSV bronchiolitis or pneumonia, as are those with congenital heart disease resulting in compromised pulmonary circulation.

RSV infections result in an estimated 500,000 emergency department visits and 1.5 million clinic visits each year in children under 5 years of age, according to the U.S. Centers for Disease Control and Prevention (CDC).² A large CDC surveillance study found RSV was associated with 20 percent of hospitalizations, 18 percent of emergency department visits and 15 percent of office visits for acute respiratory infections in children under 5 years of age.³

A subsequent CDC analysis of U.S. hospital discharges over a 10-year period found that the RSV-related LRTI disease burden falls most heavily on young infants, with 26 hospitalizations per 1,000 infants under age 1 year, dropping more than 10-fold to 1.8 per 1,000 children between ages 1 and 5 years. While estimates vary, RSV infection accounts for as few as 100 to several hundred deaths annually among infants younger than 1 year old.^4,5

Older adults and those with chronic illnesses. The subgroups of adults at high risk of LRTI following RSV infection are in some respects the mirror image of infants and high-risk toddlers. CDC estimates that more than 177,000 adults, mostly older and nonelderly adults with chronic lung or heart disease or compromised immunity, are hospitalized, and 14,000 succumb to RSV infection each year.⁶ The most serious complications potentially leading to death include:

• Pneumonia
• Exacerbation of chronic obstructive pulmonary disease (COPD) symptoms
• Exacerbation of asthma symptoms
• Congestive heart failure

A landmark study that prospectively followed separate cohorts of healthy elderly adults and high-risk adults living in Rochester, N.Y., found that, over the four-year surveillance period, RSV infection accounted for 10.6 percent of all hospitalizations for pneumonia, 11.4 percent for COPD, 5.4 percent for congestive heart failure and 7.2 percent for asthma.⁷

Just under one-fifth of healthy elderly patients who contracted RSV made a physician office visit, compared to nearly 30 percent of RSV-infected high-risk patients. But more tellingly, nine percent of high-risk RSV-infected patients visited the emergency room (ER) and 16 percent were hospitalized, while none of the RSV-infected healthy elderly patients required an ER visit or required hospitalization. Two RSV-related deaths occurred among 56 RSV-infected individuals in the high-risk cohort, and none among 46 RSV-infected individuals in the healthy elderly cohort. Nonetheless, RSV infection can infrequently result in serious LRTIs in generally healthy elderly adults.

RSV Vaccines Are Finally In Sight

A number of RSV vaccine development strategies have been pursued over the more than six decades since this enveloped virus was first identified in 1956 (Table). For older adults, three vaccination approaches that employ the RSV prefusion F (preF) protein — nucleic acid, subunit and vector-based vaccines — are currently being investigated in older adults. Stabilized preF subunit vaccines are also in late-phase development for maternal vaccination to passively transfer neutralizing anti-RSV antibodies across the placenta to the maturing fetus in the gestational third trimester.

But the first investigational RSV vaccine tested a half-century ago, a formalin-inactivated whole virus preparation (FI-RSV) with an alum adjuvant, foretold the development challenges that lay ahead. This vaccine not only failed to induce neutralizing antibodies or protect vaccinated infants,⁸ but unexpectedly, vaccinated infants infected with RSV over the subsequent winter season experienced more pronounced disease than nonvaccinated infants. At one participating center, more than 80 percent of infected FI-RSV vaccine recipients required hospitalization, compared to just five percent of infected controls. A subsequent clinical trial using parenterally administered live RSV also failed to confer protection, but enhanced RSV disease did not occur.⁹

Most currently investigated vaccines are designed to induce humoral and T cell-mediated immunity against just one of the 11 proteins encoded by this single-stranded RNA virus: the F (fusion) transmembrane glycoprotein, which facilitates membrane fusion and viral penetration into the host cell. Unlike extensive antigenic variation seen in the G transmembrane glycoprotein, which is involved in viral attachment to the target cell, the F protein is highly conserved with respect to its amino acid sequence, making it an attractive target for vaccine development.

GlaxoSmithKline F glycoprotein antigen vaccine (RSVPreF3). With a focus on protecting adults aged 60 years and older at risk for serious RSV disease, GlaxoSmithKline (GSK) has developed a recombinant intramuscular (IM) subunit RSV preF glycoprotein antigen vaccine, called “RSVPreF3,” that is combined with the company’s proprietary AS-1 adjuvant now used in several licensed GSK vaccines.

In June 2022, GSK announced “positive headline results” from a prespecified interim analysis of its ongoing Phase III, multinational, observer-blind AReSVi 006 trial, with no unexpected safety concerns. Approximately 25,000 participants aged 60 years and older in the U.S., Canada and 15 other countries were randomized to receive a single dose of the RSVpreF3 vaccine or placebo.¹⁰ Results from this trial investigating the immunogenicity, safety, reactogenicity and persistence of the vaccine candidate will be presented in a peer-reviewed journal and at an upcoming scientific meeting.¹¹

RSVPreF3 is the first candidate RSV vaccine to show statistically significant and clinically meaningful efficacy in older adults. Further, the magnitude of its effect was consistent across both RSV A and B strains, and in individuals aged 70 years and older. “These [soon to be disclosed] data suggest our RSV vaccine candidate offers exceptional protection for older adults from the serious consequences of RSV infection,” said Chief Scientific Officer and R&D President Hal Barron, MD. “Given the importance of these data, we plan to engage with regulators immediately and anticipate regulatory submissions in the second half of 2022.”

GSK is additionally investigating a promising immunization strategy in expectant mothers to protect their young infants against serious RSV-mediated pulmonary disease. A recently completed Phase II trial randomized a total of 534 pregnant women to receive a single IM dose of an unadjuvanted form of RSVPreF3 or a saline placebo. Investigators examined titers of anti-RSV antibodies that crossed the placenta into the newborn, as well as percentages of infants with RSV-associated severe LRTI from birth to day 181 post-birth; their findings are expected to be presented shortly.¹²

Pfizer bivalent prefusion F vaccine (RSVpreF). Highly encouraging results have been reported from a Phase IIa study of Pfizer’s RSVpreF vaccine candidate in 62 healthy adult volunteers 18 to 50 years of age, who were randomized to receive an IM injection of either the vaccine or placebo, followed 28 days later by intranasal inoculation with RSV A Memphis 37b challenge virus.¹³ RSVpreF achieved protective efficacy of 86.7 percent (95 percent confidence interval 53.8 to 96.9 percent) for symptomatic RSV infection, confirmed by absence of any detectable viral RNA on at least two consecutive days. The median area under the curve for RSV viral load (expressed as hours x log10 copies per milliliter) was 0.0 in the vaccine group and 96.7 in the placebo group. These findings coincided with a large increase in RSV group A-neutralizing titers 28 days after injection in vaccine group subjects, but not in placebo group subjects. No serious adverse events were observed in either group.

Moderna messenger RNA vaccine (mRNA-1345). The U.S. Food and Drug Administration (FDA) has granted this novel vaccine candidate a fast track designation for adults aged 60 years and older. Similar to its COVID-19 antigen vaccine, mRNA-1345 uses Moderna’s messenger RNA delivery technology to direct production of the preF glycoprotein in cells of the vaccinated individual.

A Phase II/III trial of mRNA-1345 is now in progress. The Phase II segment is randomly assigning between 400 and 2,000 participants to receive a single injection of either mRNA-1345 or placebo. In the Phase III segment, between 32,000 and 34,000 participants aged 60 years and older will be randomized 1:1 to receive the vaccine or placebo, and followed for 12 months postinjection to assess the ability of mRNA-1345 to prevent a first episode of RSV-caused LRTI.¹⁴

Moderna is also conducting a trial involving co-administration of mRNA-1345 with a seasonal influenza vaccine (Afluria Quadrivalent), and separately with the company’s SARS-CoV-2 vaccine, to evaluate the impact of co-administration on immune response to each of these vaccines.

CyanVac/Blue Lake PIV5-based vector vaccine encoding RSV-F protein. The clinical-stage vaccine developer Blue Lake Biotechnology and parent company CyanVac are developing a novel intranasally delivered RSV vaccine, named BLB-201, that uses a proprietary attenuated parainfluenza virus 5 (PIV5)-based vector to express the full-length RSV-F protein. BLB-201 is being developed for the prevention of RSV disease in adults over age 60 years and children under age 2 years. Administered for decades to dogs as part of combination distemper and kennel cough vaccines, this attenuated PIV5 vector is not known to cause disease in humans.

In July 2022, Blue Lake initiated a Phase I trial to assess the safety and immunogenicity of BLB-201 in 15 healthy young adult volunteers aged 18 to 59 years, and the same number of healthy older adults aged 60 to 75 years.15,16 The trial is designed to assess the safety, tolerability and immunogenicity of a single dose of BLB-201. Based on preclinical studies showing that it is immunogenic and prevents RSV infection in animal challenge studies, BLB-201 has received fast track designation from FDA.

Passive Immunotherapy for Healthy and High-Risk Infants

Because the relative immaturity of the immune systems of infants under age 2 years can limit the value of vaccination against RSV, most drug developers have settled on a passive immunotherapy strategy to prevent LRTI in this population. Since its approval in 1998, Sobi’s Synagis (palivizumab) monoclonal antibody against the RSV F protein has been prescribed for the prevention of LRTI in premature infants (less than 35 weeks gestational age) aged 6 months or younger at the start of the RSV season, as well as children under age 24 months with significant congenital heart disease (CHD) or recently treated bronchopulmonary dysplasia (BPD). But Synagis’ applicability beyond these narrow indications has been limited by the requirement to administer IM doses every month throughout the five-month RSV season.

AstraZeneca/Sanofi long-acting mono-clonal antibody. In collaboration with Sanofi, which will commercialize the product if approved, AstraZeneca is in late-stage development of nirsevimab, a single-dose, long-acting antibody intended to provide protection against RSV-caused LRTIs both for all infants experiencing their first RSV season, and for infants with pulmonary or cardiac conditions that place them at increased risk.

In 2020, findings from a Phase IIb trial of nirsevimab in 1,453 healthy preterm infants (29 weeks to 34 weeks 6 days of gestation) showed a 70.1 percent lower incidence of medically attended LRTIs — mainly bronchiolitis and pneumonia — with a single prophylactic dose of nirsevimab than with placebo (2.6 percent versus 9.5 percent). The incidence of hospitalization for RSV-associated LRTI was 78.4 percent lower with nirsevimab than with placebo (0.8 percent versus 4.1 percent). Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions.¹⁷ The Phase II/III MEDLEY trial documented a similar safety and tolerability profile for nirsevimab compared to palivizumab treatment when administered to preterm infants or those with chronic lung disease or congenital heart disease entering their first RSV season.¹⁸

Subsequently, the multinational Phase III MELODY study demonstrated that, compared to placebo injection, a single IM injection of nirsevimab achieved a 74.5 percent reduction in the incidence of LRTI caused by RSV in healthy preterm (≥35 week gestational age) and term infants entering their first RSV season (1.2 percent versus 5.0 percent; P<0.001).¹⁹

In a pooled post-hoc analysis, blood samples taken from infants dosed with nirsevimab exhibited RSV neutralizing antibodies roughly 50-fold higher than baseline at day 151 post-dose. RSV neutralizing antibody levels remained greater than 19-fold higher than levels in placebo recipients, with no known RSV infection through day 361, suggesting protection could extend beyond day 151.

Merck long-acting monoclonal antibody. MK-1654, Merck’s anti-RSV antibody product, is also being investigated as a single-injection prophylactic treatment to prevent RSV-associated LRTI in 1) all infants entering their first RSV season and 2) young children in their second year of life who are at high risk of RSV disease. This IgG antibody binds to the highly conserved site IV of the F glycoprotein on RSV, and has increased potency compared to Synagis. MK-1654 attains its extended circulating half-life by means of three amino acid substitutions that augment recycling through the neonatal Fc receptor.

A Phase IIb/III randomized, placebo-controlled trial is now enrolling up to 3,300 healthy preterm and full-term infants to assess whether MK-1654 can significantly reduce the incidence of medically attended LRTIs over 150 days following injection with the vaccine. The study is expected to be completed in 2024.²⁰

Findings from these trials have not yet been reported, but the company’s model-based meta-analysis predicts a high probability that a single dose of ≥75 mg of MK-1654 will result in prophylactic efficacy in treated infants over the five-month RSV season.²¹

Meeting an Under-Recognized Need

Until recently, the morbidity and mortality burden associated with RSV infection had been underestimated at both ends of the age spectrum, infectious disease experts noted in a recent review. Perhaps most surprisingly, modeling studies now estimate that the overall RSV disease burden is similar to the burden of seasonal influenza in adults older than 65 years.²²

No fewer than six vaccines and two monoclonal antibody products are now in Phase III clinical testing, with numerous others in Phase I or II development. Notably, AstraZeneca’s nirsevimab is expected to be approved within the next year to two years;²³ the company’s marketing authorization application was accepted for review earlier this year by the European Medicines Agency.

Thanks to the industry’s efforts to advance an array of innovative new vaccines and antibody therapies that resolve the shortcomings of their predecessors, safe and effective prophylactic treatments for RSV may finally be close at hand.