adult RSV vaccine effectiveness/concerns

 

a new report found that the respiratory syncytial virus (RSV)-related hospitalizations and emergency department visits decreased dramatically with the new RSV vaccination in high-risk adults aged 60 years or older  (see rsv vaccine effectiveness JAMA2024 in dropbox, or doi:10.1001/jamanetworkopen.2024.50832)

 

Details:

-- 7047 patients with low respiratory tract disease (LRTD)-related hospitalizations or emergency department (ED) encounters were included in this retrospective case-control study with a test negative design to assess the effectiveness of RSV vaccination, in the Kaiser Permanente of Southern California (KPSC) database, from 2023-2024

    -- KPSC includes 4.8 million members, with 11.1 being at least 60yo

-- RSVpreF vaccination (Abrysvo) was assessed during the first RSV season after vaccine licensure and 21 or more days before LRTD

-- cases: patients who were RSV-positive with LRTD events

-- controls (2 prespecified cohorts):

    -- "strict controls" (primary analysis): LRTD events that were negative for RSV, human metapneumovirus (HMPV), influenza, and SARS-C0V-2  (vaccine-preventable diseases); and they were positive for a nonvaccine preventable disease comprising adenovirus, coronavirus (229E, HKU1,NL63, or C43), human rhinovirus/enterovirus, parainfluenza 1-4, Chlamydia pneumoniae, and Mycoplasma pneumoniae

        -- this strict control was established to control for bias associated with vaccine preventable disease and for the potential vaccine effectiveness against HMPV (though there is no direct vaccine to prevent HMPV)

    -- "broad" controls: RSV-negative LRTD events, regardless of other identified causes (and also including those testing negative for all pathogens)

        -- this broad control was used as a more-encompassing sensitivity analysis

-- in addition, there was "enhanced specimen collection", salvaging clinical respiratory swabs not tested for RSV during routine care (ie, respiratory specimens assessed specifically for SARS-CoV-2 and influenza that were later found and retested for RSV)

    -- salvaged specimens were more often from earlier in the season and mostly done in non-Hispanic white patients, those with few comorbidities, those who had the fewest health care encounters in the prior year, and those presenting to the ED

 

-- mean age 76.8 years (57% were at least 75yo); 3819 (54.2%) were female; 839 (11.9%) were non-Hispanic Asian or Pacific Islander, 2323 (33.0%) were Hispanic, 1197 (17.0%) were non-Hispanic Black, and 2602 (36.9%) were non-Hispanic White

-- 998 (14.2%) were immunocompromised; and 6573 (93.3%) had 1 or more Charlson comorbidities, 72% had at least 3

-- specific comorbidities: peripheral vascular disease 68%, COPD 50%, kidney disease 42%, heart failure 37%, malignant neoplasm 17%, MI 16%, cerebrovascular disease 14%, dementia 12%,moderate-to-severe liver disease 2%, AIDS/HIV 0.3%

-- diabetes: HbA1c at least 7.5% in 16%, <7.5% in 34%, no diabetes in 48%

-- other markers of poor health: at least 1 hospitalization in the prior year in 39% (with 18% having >1); at least 1 ED visits in prior year in 62% (with 38% having >1); outpatient visits 71% at least 10

-- immunocompromised: 998 patients (14%)

-- exclusions: non-RSVpre-F vaccine recipients (eg those getting Arexvy, a different RSV vaccine, as noted below) or those who had receive the RSV vaccine <21 days before the LRTD encounter (who may have had suboptimal immunity from the vaccine)

 

-- main outcome: estimated RSVpreF vaccine effectiveness (VE) against first episode of RSV-related LRTD hospitalization or ED visit.

        -- Additional outcomes evaluated in this group included RSV-related LRTD hospitalizations, RSV-related LRTD hospitalizations among patients with high-risk chronic medical conditions, RSV-related LRTD ED events, RSV-related severe LTRD hospitalizations (ie, supplemental use of oxygen) and ED events

 

Results:

-- 8085 patients (77% of the total) had a nasal or nasopharyngeal swab: 5639 of them were tested directly for RSV and 4236 had RSV testing from salvaged specimens

-- 7047 LRTD events had tested specimens (62%) and were included in the analysis 

    -- most common LRTD diagnosis: pneumonia

-- 623 of the 7047 (8.8%) tested positive for RSV

-- 223 (3.2%) of the total population received the RSVpreF vaccine

    -- those most likely to be vaccinated: non-Hispanic Asian or Pacific Islander and non-Hispanic white patients, and those with at least 10 outpatient encounters in the year before LRTD

    -- those least likely to be vaccinated: those with peripheral vascular disease, COPD or diabetes

 

-- 27 RSV cases had viral coinfection

 

--estimated adjusted VE using strict controls was 91% (59%-98%). Using broad controls, estimated adjusted VE was 90% (59%-97%) [ie no difference]

 


other findings: no difference in VE by LRTD hospitalizations or ED visits, whether there were underlying high-risk chronic medical conditions, or severity of RSV vaccination

 


Commentary:

-- prior studies have found RSV vaccine efficacy against LRTD, however the studies had relatively few patients at least 75 years old or those with comorbidities.  This study was designed to assess a larger number of patients who were sicker and had RSV-related hospitalizations and emergency department visits

-- RSV infection in older adults is a common cause of severe respiratory disease. In the US, 160,000 people at least 65yo are hospitalized for RSV infections and 120,000 have ED visits annually

-- Notably, RSV infections can be associated with an increased risk of acute cardiac events: a study in 2024 found that of 6248 patients hospitalized with an RSV infection, 22% had an acute cardiac event (mostly acute heart failure, in 16%), which happened much more so in those with underlying cardiovascular disease, a group that also had twice the risk of severe outcomes: https://pubmed.ncbi.nlm.nih.gov/38619857/ and https://www.sciencedirect.com/science/article/pii/S0735109718304856?via%3Dihub 

 

-- on June21, 2023 the FDA approved a single dose of this RSVpreF vaccine (Respiratory Syncytial Virus Perfusion F) for people at least 60yo, with shared decision-making.  the FDA was apparently hesitant to have a stronger recommendation because of lack of vaccine effectiveness regarding RSV-related hospitalization and among high-risk groups. Hence this study...

-- current FDA recommendations were updated in 2024 to include all people 75yo or older

 

-- there are 3 approved RSV vaccines (https://www.cdc.gov/vaccines/vpd/rsv/hcp/older-adults.html)

    -- Arexvy: From GSK, FDA approved May 2023: a recombinant RSV F protein antigen, stabilized in the prefusion conformation (preF), and with AS01E adjuvant, based on the RSV-A subtype

    -- mResvia: From Moderna, FDA approved in May 2024, a recombinant RSV F protein antigen, stabilized in the prefusion conformation (preF), based only on the RSV-A subtype

    -- Abrysvo: From Pfizer, FDA approved May 2023, nucleoside modified mRNA encoding the RSV F glycoprotein, based on both the RSV-A and RSV-B subtypes

-- these vaccines can be administered with one or more other vaccines at the same visit, though there might be increased local or systemic reactogenicity (however, effectiveness data are mixed on the co-administration with influenza vaccine)

-- so, what are the differences between the vaccines:

    -- Abrysvo (the one used in this study) is based on both RSV types; Arexzy and mReservia are based only on RSV-A subtype

        -- But Arexvy does provide protection against both RSV A and RSV B serotypes in some studies

    -- mReservia did not have much effect on people >75yo in a phase 3 trial, and had an 80% decrease in hospitalization for RSV-associated illness 

    -- Arexvy, per the FDA has an 83%  decreased risk of developing RSV-associated LRTD

        -- for FDA info on the Arexvy and Abrysvo, see https://www.cdc.gov/acip/grade/protein-subunit-rsv-vaccines-older-adults.html; for mResvia, see https://www.cdc.gov/acip/grade/mrna-rsv-vaccine-older-adults.html

   -- BUT, one should be careful to actually compare these numbers directly, since the studies are not direct comparisons and, for each vaccine, there were different groups of patients with different diseases/disease severities, etc

    -- and, there is zero likelihood of a strong, well-designed randomized controlled trial to see which vaccine is the best for which person (which might vary based on the 2 groups: 60+ yo with comorbidities, and everyone at least 75yo); there may well be a best vaccine, but the other 2 drug companies would not like to see those results!!!!  could affect their "bottom line".......

    -- though, perhaps most significantly, mReservia is the only one with a pronounceable name


-- then there is the issue of adverse effects of the RSV vaccines (
https://www.cdc.gov/mmwr/volumes/73/wr/mm7321a3.htm#T3_download):

    -- the current study above did not list (or likely have information) about adverse effects in this retrospective study

    -- the FDA report that compared Arexvy and Abrysvo  found that the minor adverse  effects of Arexvy and Abrysvo were pretty similar overall but the injection-site problems were more prevalent with the former

    -- and there is that big issue of Guillain-Barre Syndrome (GBS): "Among the 28 reports of GBS after vaccination that met case definition, 13 (46.4%) were after GSK vaccine Arexvy (1.8 reports per 1 million doses administered), and 15 (53.6%) were after Pfizer vaccine Abrysvo (4.4 reports per 1 million doses administered) among persons aged ≥60 years. no info on the mReservia vaccine. of course, GBS is quite rare, but still a bummer to get

 

--this study affirms that in a sick patient population of people >60yo (57% being >74yo), RSV infection was >90% effectively reduced by the RSVpreF vaccine (the above results found that those with comorbidities the same 90% vaccine effectiveness, but the numbers of patients vaccinated in this study who got documented RSV infections was small and non-vaccine studies have found that those with more comorbidities getting RSV infections do worse: eg https://pubmed.ncbi.nlm.nih.gov/37970679/ ).

-- this overall result was similar to the prior clinical trial RENOIR with the same RSVpreF vaccine (https://www.nejm.org/doi/full/10.1056/NEJMoa2213836 ) of those >60yo in those but with much less severe comorbidities, finding a 67% decrease in those developing RSV infection having at least 2 signs/symptoms of RSV and 86% for at least 3 RSV symptoms (ie, similar decrease in patients getting more severe RSV infection of about 90% with vaccination, but also very few cases assessed); adverse effects were minimal and mild, related to the injection itself

 

Limitations:

--they did include remnant swabs from patients who were tested for influenza and covid, since the overall testing for RSV was quite low in their strict analysis. this could introduce an important bias, since the group tested for covid or influenza may be different than in a randomized trial (were they sicker than those not considered for this testing?, did they present with different symptoms??), though their findings by incorporating this large group of patients did not change the results

    -- that being said, the numbers of patients who were hospitalized with RSV who had received the vaccine was really small (13 in total, which might be related to the later rollout of RSV vaccination at KPSC)

    -- and not all patients with LTRD had RSV testing (38% of LRTD patients were not included in the study), again potentially distorting the results (was it only the really sick ones who were tested??)

-- they only used the RSVpreF (after all, this was a drug company sponsored study.....), so unclear if results pertain to the other RSV vaccines

-- this study did try to deal with the issue of the results being contaminated from other vaccine-preventable infections, though we do know that there are multiple viruses involved simultaneously in respiratory viral infections pretty often. The numbers of infections overall in this study were too low to get accurate information on the results of vaccination in those with multiple viral infections vs just RSV: 27 of the 223 patients (12%) had RSV plus another viral infection, muddying the waters a bit

-- overall, there is a quite low sensitivity of nasopharyngeal/nasal swab reverse transcription PCR testing in adults (about 50% of RSV cases are not detected). why was this so low? was it from poor technique? or characteristics or quantity of the virus? how would this affect the generalizability of the results, since the sensitivity of the PCR is so low? 

-- this was a quite sick population with many comorbidities and lots of health care encounters in the year prior to the study onset. this might not reflect the effectiveness of the vaccine in less sick patients, despite their findings otherwise

    -- eg, some of the comorbidities included very few people (only 23 with HIV/AIDS and 2 in the strict analysis; only 120 with moderate or severe liver disease and 9 in the strict analysis), limiting generalizability to these patients 

— the enhanced group of salvaged specimens did not reflect the specifics of the overall group and could distort the results (they were more often assessed earlier in the season, mostly in non-Hispanic white patients, those with few comorbidities and those who had the fewest health care encounters in the prior year); this enhanced group included 43% of the total

-- only 223 (3.2%) of the total population received the RSVpreF vaccine. the results would be more rigorous in a larger study, especially given the above concerns about their generalizability to the overall population

    -- and the distribution of those vaccinated did vary by demographics and comorbidities, again raising issues of generalizability

 

so:

-- despite the above-noted limitations, it does appear that the RSV vaccines are really quite potent in preventing bad outcomes of RSV-associated lower respiratory tract disease

-- as with all vaccines, there are relatively frequent local adverse effects at the site of the injection, with a very rare likelihood (though should be mentioned to patients...) of Guillain-Barre syndrome, and the incidence of GBS seems to be in-line with influenza vaccine (per the CDC, "The data on the association between GBS and seasonal flu vaccination are varied and inconsistent across flu seasons. If there is an increased risk of GBS following flu vaccination, it is small, on the order of one to two additional GBS cases per million doses of flu vaccine administered")

-- there is a significant mortality from RSV infection in adults >60yo, perhaps in the 9% range for hospitalized patients (https://pmc.ncbi.nlm.nih.gov/articles/PMC10911257/)

   -- so, the perspective is that LRTD can be a very severe or fatal in RSV-associated infection, statistically supporting the use of the vaccine in those at high risk for these complications

-- and, it seems it is a one-time injection (at least for now)

-- also, by the way, the CDC also recommends that the Abrysvo vaccine (no mention of the others) be given to pregnant people during 32-26 weeks of pregnancy, to protect the infant (earlier immunization is discouraged because of waning antibody titers passed to the neonate)

 

geoff

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