Just Arrived: A Trio of Active and Passive Vaccines Against RSV

For decades, respiratory syncytial virus (RSV) — a leading cause of serious lower respiratory tract disease (LRTD) in infants and older individuals — has defied the best efforts of vaccine makers to bring it to heel. Now over a span of less than three months between May and July of this year, U.S. marketing approvals of two novel, highly targeted RSV vaccines and a human RSV monoclonal antibody product have finally ended that long record of research futility.

Available in time for this fall/winter 2023-2024 RSV season, these three new agents offer the potential to importantly cut the annual toll in illness, death, healthcare costs and broader economic costs attributable to RSV.

The RSV Disease Burden

Most children and adults infected with RSV experience only minor cold-like symptoms, including rhinorrhea, coughing and sneezing, which generally resolve on their own within a week or two. But this is not the case for infants entering the RSV season within their first six months of life, for young children with congenital pulmonary or heart disease, or for older adults, particularly those with a long list of chronic comorbidities. All are at sharply increased risk for their RSV infection to progress to severe LRTD.

Each year among young children, RSV accounts for at least 57,000 hospitalizations, 500,000 emergency department visits and one-and-a-half million outpatient clinic visits.¹ The U.S. Centers for Disease Control and Prevention (CDC) estimates that RSV infection may be associated with up to 20 percent of hospitalizations and 18 percent of emergency department visits for acute respiratory infections in children under 5 years of age.²

A separate CDC analysis of U.S. hospital discharges over a 10-year period found the RSV-related disease burden falls most heavily on very young infants, with 26 LRTD-related 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. RSV additionally accounts for about 100 to several hundred deaths annually among infants under 1 year of age.³

In adults, it is estimated that RSV infections result in between 60,000 and 160,000 hospitalizations of older adults each year, and 6,000 to 10,000 deaths. Adults at highest risk for severe RSV infection and its complications include those over age 60, and those with chronic heart or lung disease, compromised immunity and certain other underlying health conditions, including diabetes, asthma and chronic kidney disease.⁴ The most serious complications secondary to RSV infection include pneumonia, congestive heart failure and exacerbations of chronic obstructive pulmonary disease or asthma symptoms.

A landmark study that prospectively followed separate cohorts of healthy elderly adults and high-risk U.S. adults found nearly 30 percent of high-risk RSV-infected patients made a physician office visit, more than 50 percent higher than the visit rate for generally healthy elderly patients who contracted RSV. But more tellingly, nine percent of high-risk RSV-infected patients made an emergency room (ER) visit and 16 percent were hospitalized, while none of the RSV-infected healthy elderly patients required an ER visit or hospitalization. Nevertheless, RSV infection can infrequently result in serious lower respiratory tract infections (LRTIs) in generally healthy elderly adults.⁵

Decades of Vaccine False Starts

Since RSV was first discovered in 1956, all past attempts to develop safe and effective RSV vaccines have proven unsuccessful. Clinical testing of an early inactivated form of RSV in the mid-1960s proved disastrous when 80 percent of vaccinated children in one study were hospitalized and two toddlers died when they contracted the virus. Later research revealed antibodies produced by the children’s immune systems bound to RSV but did not neutralize it, instead triggering a cascade of events leading to inflammation and lung tissue damage. This phenomenon, called antibody-dependent enhancement, occurs when the body produces antibodies that fail to confer adequate protection and instead act to exacerbate the infection.

Over the following decades, most vaccine development has focused on the RSV F antigen, which facilitates membrane fusion and viral penetration into the host cell. But progress continued to stagnate until a molecular biologist at the National Institutes of Health Vaccine Center applied atomic structure mapping to show that the F protein has distinct prefusion and postfusion conformations.⁶ It was subsequently determined that antibodies against the prefusion F (preF) conformation effectively neutralize the circulating form of the virus before it fuses to cells, while those against the postfusion protein shape do not.

New RSV Vaccines Approved for Older Adults

Additional research resulted in the isolation of a potent RSV-neutralizing antibody against a highly conserved epitope on preF that effectively blocks viral fusion and entry into host cells. After 50 years of futility, these discoveries led directly to the development and licensure, in May of this year, of the first two RSV vaccines approved for the prevention of LRTD in individuals aged 60 years and older: GlaxoSmithKline’s Arexvy and Pfizer’s ABRYSVO (Table 1).

Table 1. New FDA Approvals of Active and Passive Immunotherapies for the Prevention of RSV-Caused Lower Respiratory Tract Disease (LRTD) in Infants and Older Adults

AREXVY (GlaxoSmithKline [GSK]). The first-ever RSV vaccine to be approved in the U.S., GSK’s recombinant subunit preF glycoprotein antigen vaccine is combined with the company’s proprietary AS-01 adjuvant system incorporated into several licensed GSK vaccines. AREXVY (previously RSVPreF3) is administered as a single intramuscular (IM) dose.

The U.S. Food and Drug Admini-stration’s (FDA) approval of AREXVY is based on safety and efficacy findings from the pivotal AReSVi-006 Phase III trial conducted in adults ≥60 years of age at 275 sites in the U.S. and 16 other countries. Over a median follow-up of 6.7 months, vaccine efficacy against RSV LRTD was 82.6 percent (96.95 percent confidence interval [CI], 57.9 to 94.1), with seven cases of RSV-LRTD in the vaccinated group (n = 14,467), compared to 40 cases in the placebo group (n = 14,499). Vaccine efficacy (VE) against severe RSV-LRTD, defined as an RSV-associated LRTD episode preventing normal everyday activities, was 94.1 percent, with just a single case in vaccinated subjects versus 17 cases in placebo-treated subjects.⁷

AREXVY was well-tolerated; most observed adverse events included injection site pain, fatigue, myalgia, headache and arthralgia, all of which were generally mild to moderate and transient. However, two South African study participants in a separate smaller trial developed acute disseminated encephalomyelitis (ADEM) seven and 22 days after receiving AREXVY concomitantly with a seasonal influenza vaccine, and a Japanese patient in a second trial was diagnosed with Guillain-Barré syndrome (GBS) nine days after receiving AREXVY.⁸ GSK will conduct a postmarketing study to identify any signals of serious risks for ADEM and GBS.

ABRYSVO (Pfizer). Encouraged by an earlier study showing 87 percent protective efficacy against symptomatic RSV infection in healthy volunteers intranasally inoculated with the live virus,⁹ Pfizer investigated its own RSV prefusion F antigen vaccine (RSVPreF) in the Phase III randomized, placebo-controlled RENOIR trial in adults ≥60 years of age. ABRYVSO is an unadjuvanted bivalent preF vaccine; the two preF proteins were selected to optimize protection against both RSV A and B strains.

At data cutoff, more than 34,000 participants were enrolled at 240 clinical sites in seven countries. RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1,000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1,000 person-years), translating in VE of 62.1 percent (95 percent CI, 37.1 to 77.9).¹⁰

RSV LRTD with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1,000 person-years) and 33 participants in the placebo group (3.58 cases per 1,000 person-years), for a VE of 66.7 percent (96.66 percent CI, 28.8 to 85.8). RSV LRTD with at least three signs or symptoms occurred in just two and 14 cases in the vaccine and placebo groups, respectively, for a VE of 85.7 percent (96.66 percent CI, 32.0 to 98.7). Very similar rates of adverse events and severe adverse events were reported for both treatment arms.

Pfizer plans to initiate additional clinical trials to evaluate ABRYVSO in healthy children ages 2 to 5, children ages 5 to 18 at high risk for LRTD due to underlying medical conditions, and immunocompromised adults 18 and older who are at high risk for LRTD.

In early August, GSK filed a lawsuit against Pfizer in U.S. court, alleging ABRYSVO infringes four of its patents related to recombinant RSV antigens used in Arexvy, as well as the methods used to create this and other vaccine components.11 GSK has requested a jury trial and is seeking monetary damages, including lost profits and royalties. The United Kingdom drugmaker is also asking a judge to prevent Pfizer from manufacturing and selling ABRYSVO in the U.S. for adults aged 60 and older.

Pfizer responded that it “is confident in its intellectual property position and will strongly defend its right to bring its innovative RSV vaccine ABRYSVO to patients.”¹¹

Meanwhile, both GSK and Pfizer have launched public awareness campaigns targeting Americans age 60 and older (Figure 1), particularly those living with chronic health conditions associated with increased risk of severe RSV disease.

Figure 1. Pfizer and GSK Promotional Materials Encouraging Persons 60 and Older to Inquire About RSV Vaccination

Passive Immunotherapy for Preterm and High-Risk Infants

Because of the immaturity of antibody-mediated immunity in the first months of life, active immunization with an RSV vaccine cannot confer adequate protection against RSV-associated LRTD.

With this in mind, scientists at MedImmune, now part of AstraZeneca, developed nirsevimab (formerly MEDI8897), a highly potent human recombinant human monoclonal antibody (MAb) that targets a highly conserved site of the prefusion conformation of the RSV fusion (F) protein. Additionally, a substitution of three amino acids in the Fc domain of nirsevimab extends its half-life three-fold, allowing for a single IM dose of this long-acting MAb to cover a typical five-month RSV season.

Nirsevimab has been shown to neutralize a diverse panel of RSV A and B strains, with more than 50-fold higher activity than palivizumab (Synagis), another MedImmune-developed anti-RSV MAb approved in 1998 for the prevention of serious LRTD in premature infants (≤35 weeks gestational age) and children with bronchopulmonary dysplasia or congenital heart disease.

Approved in July and brand-named Beyfortus, nirsevimab is indicated for the prevention of RSV LRTD in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Beyfortus will be manufactured by AstraZeneca and distributed through Sanofi, and will be available ahead of the upcoming 2023-2024 RSV season.

Two key clinical studies have demonstrated the ability of a single dose of Beyfortus to achieve a 70 to 75 percent reduction in the risk of medically attended LRTI in preterm and full-term infants, as well as infants with pulmonary or cardiac conditions placing them at high risk for LRTI (Table 2).

Table 2. Phase IIb and Phase III Clinical Study Findings Documenting Efficacy of Beyfortus (nirsevimab)
for Prevention of RSV-Related Lower Respiratory Tract Infection

In addition to a 70 percent reduction in risk of bronchiolitis, pneumonia and other medically attended LRTIs, preterm infants enrolled in a Phase IIb study (Study 03) who received a single prophylactic dose of Beyfortus experienced a 78.4 percent lower incidence of hospitalization (0.8 percent versus 4.1 percent) than those given placebo.¹² 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.¹³

Subsequently, a multinational Phase III study (Study 04) 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 weeks gestational age) and term infants entering their first RSV season (1.2 percent versus 5.0 percent; P<0.001).¹⁴

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.

In addition, real-world data from the Phase IIIb HARMONIE study documented an 83.2 percent (95 percent CI, 67.77 to 92.04) reduction in hospitalizations due to RSV-related LRTD in infants under 12 months of age who received a single dose of nirsevimab, compared to infants who received no RSV intervention.15

This clinical trial, which recruited more than 8,000 infants at nearly 250 sites across France, the United Kingdom and Germany, also documented a 58 percent lower incidence of all-cause hospitalizations in infants who received a single dose of nirsevimab. “This means the overall burden on healthcare systems could be reduced significantly if all infants receive nirsevimab,” Sanofi said in an announcement of its HARMONIE study findings.¹⁶

Young Infant RSV Protection by Maternal Vaccination

A recent multinational investigation of clinical RSV infection in children under age 2 years has confirmed what one would expect: The highest rate of RSV LRTI occurs in infants under 6 months of age. The incidence of first-episode RSV-LRTIs at age 0 to 5 months was one-third higher than the incidence at age 6 to 11 months, and more than 2.5-fold higher than at age 12 to 23 months.¹⁷

But more importantly, the incidence rates of both severe RSV-LRTIs and RSV-related hospitalization were many-fold higher over the first six months than the following 18 months of life (Figure 2).¹⁷ This owes both to the immaturity of immune defenses in very young infants and the high surface-to-volume ratios in their still-developing airways. Because nearly all pulmonary airways and alveoli are present at birth, the bronchiolar lumen size in young infants is smaller relative to that of an adult and thus more prone to obstruction.¹⁸

Figure 2. Incidence Rates of RSV-LRTIs, Severe RSV-LRTIs and Resulting Hospitalizations in Three Infant Age Cohorts

Source: Langley JM, Bianco V, Domachowske JB, et al. J Infect Dis 2022 Aug 26;226(3):374-85.

It is now well-established that exogenously administered anti-RSV MAbs like nirsevimab can protect very young infants who are unable to self-generate sufficiently protective antibody titers against RSV. However, Pfizer and other RSV vaccine developers have instead pursued an entirely different protective antibody prophylaxis strategy: RSV vaccination of pregnant women to effect transplacental transport of their anti-RSV antibodies to the maturing fetus.

Three months after FDA approval of Pfizer’s ABRYSVO for prevention of LRTD caused by RSV in persons 60 years of age and older, the vaccine received a second approval for active vaccination of pregnant women at 32 to 36 weeks gestational age for the prevention of RSV-caused LRTD and severe LRTD from birth through 6 months of age.

“Newborns and young infants — whose immune systems are still developing and are not yet strong enough to defend against infections — may now be protected from RSV from the moment of birth through maternal immunization,” said Eric A.F. Simões, MD, a MATISSE study investigator.

FDA approval for this novel indication was based on data from the pivotal Phase III MATISSE trial, which randomly assigned more than 7,300 maternal participants at 24 through 36 weeks’ gestation to receive a single IM injection.¹⁹ Within the first 90 days after birth, severe LRTI occurred in just six infants in the vaccine group and 33 infants in the placebo group, for a VE of 81.8 percent (95 percent CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth, translating into a VE of 69.4 percent.

But while ABRYVSO was judged to be efficacious at protecting infants during their first six months from severe RSV disease, there was a non-statistically significant imbalance in the number of premature births: 201 in the vaccinated group versus 169 in the placebo group, or about one percent higher.

While most preterm births had already reached 33 weeks of pregnancy and prematurity rates in both treatment arms fell below the overall U.S. population average, it still raised concerns with some FDA advisory panel members, particularly in light of GSK’s decision last year to abandon a similar clinical trial program for its investigational RSV vaccine,* after observing an increased incidence of premature deliveries compared to placebo.²⁰

After careful review of the MATISSE study data, FDA decided to address this concern over a possible risk of vaccine-related prematurity by restricting the maternal vaccination window to gestational weeks 32 to 36. In addition, using Medicaid and commercial insurance claims databases, Pfizer will conduct a postmarketing study to follow multiple safety endpoints, including rates of premature births and low birth weight at delivery.

Putting RSV Preventive Tools Into Practice

While both the GSK and Pfizer RSV vaccines are broadly indicated for the prevention of LRTD caused by RSV in individuals age 60 and older, the CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended “shared clinical decision-making” between providers and patients.²¹ The decision about whether or not to vaccinate, according to ACIP, should be based on a discussion about “the patient’s risk for disease and their characteristics, values and preferences; the provider’s clinical discretion; and the characteristics of the vaccine.”

This differs from ACIP’s recommendation of routine seasonal influenza vaccination for all age groups, including older adults. A recommendation of shared clinical decision-making reflects the fact that persons ≥60 years of age with chronic lung, cardiovascular, kidney, liver, hematologic and certain other medical conditions are at highest risk for severe RSV disease and are most likely to benefit from RSV vaccination. Additionally, the AREXVY and ABRYSVO trials were underpowered to estimate efficacy against RSV-associated hospitalization and death.

Still, according to ACIP, “prevention of LRTD, including medically attended LRTD, suggests that vaccination might prevent considerable morbidity from RSV disease among adults aged ≥60 years.”²¹ CDC says it will prioritize estimating VE against RSV-associated hospitalization, which may provide further guidance for shared decision-making between physicians and patients.

Separately, ACIP has recommended Beyfortus (nirsevimab) specifically for infants aged less than 8 months born during or entering their first RSV season, and for infants and children aged 8 to 10 months who are at increased risk of severe RSV disease entering their second RSV season.²² But this new recommendation was published the very same week that Pfizer’s ABRYSVO received its second approval for immunization of pregnant women to prevent RSV LRTD in infants in their first six months of life.

Will young infants delivered from mothers immunized with ABRYSVO experience meaningful added protective benefit from passive immunization with Beyfortus? Which adults over age 60 experience clinically meaningful benefit from RSV vaccination? Will periodic booster shots be needed, and when? The answers to these questions and more must await real-world experience. In the meantime, we all can be thankful for the extraordinary science and the considerable investments that made these products possible.