Immunology and Biotherapies

This is the main page for the CBER Vaccines and Related Biological Products Advisory Committee (VRBPAC) September 20, 2024 Meeting announcement and meeting materials.

Study demonstrates that a single-dose intranasal live-attenuated vaccine, CDO-7N-1, provides broad protection against SARS-CoV-2 and its variants by inducing potent immune responses, including neutralizing antibodies and T-cell activity, in animal models.

Despite significant advances in biologic and small molecule treatments and the emergence of combination therapies to treat inflammatory bowel diseases (IBD) a large unmet need remains to control intestinal inflammation.

Millions of pregnant women get the pitch through their OB-GYN: Put a bit of your newborn’s umbilical cord on ice,...

This study demonstrated good safety, tolerability, and immunogenicity of Ad5-S-Omicron (NB2155), a replication-incompetent human Ad5 carrying Omicron BA.1 spike, as a monovalent intranasal booster in people who previously received injected inactivated whole-virus vaccines. Most AEs related to this nasal vaccine were mild, with comparable AEs and rates as other intranasal vaccines, such as FluMist, a live-attenuated influenza virus (LAIV), and an influenza virus–vectored COVID-19 vaccine (23, 24). Interestingly, solicited AEs, including oropharyngeal discomfort and nasal congestion, appeared to be much less noticeable after the second dose. Our preliminary observation also suggested that a 2-dose regimen may confer effective protection against Omicron infection even in a high–viral load environment. For participants who reported no infections, we monitored the elevation of nasal nucleocapsid-specific sIgA from day 0 to day 118 after the first dose to identify if there were any possible asymptomatic infections. We found that only 4 out of 29 of those 2-dose participants (13.8%) had a noticeable elevation of nasal nucleocapsid-specific sIgA between day 14 and day 90 after the second dose, suggesting that they might have an asymptomatic infection, though we could not exclude if extremely close contact with the discharged material from infected people may also induce such elevation. One of the most remarkable findings was that the second dose dramatically induced nasal spike-specific sIgA against 10 SARS-CoV-2 strains ranging from wild-type, Beta, Delta, to all Omicron subvariants tested. Strikingly, the elevation magnitude of 2 doses (51.5-fold increase) was much higher than that of 1 dose (4.5-fold increase), suggesting the importance of the second dose of intranasal booster. Our result differed from clinical studies of 2 nasal vaccines using simian-derived adenoviral vectors, AZD1222 (ChAdOx1 nCoV-19) and BBV154. Using the same MSD method for detecting spike-specific IgA, AZD1222 only generated a >3-fold elevation of nasal IgA against wild-type spike in 18.2% of participants but no IgA against other spikes (25). BBV154 induced a 1.56-fold elevation of salivary IgA against wild-type spike on day 42 over day 0 as measured by ELISA but had no reported effect on nasal IgA (26). Of note, ChAdOx1 is SAdY25 isolated from fecal samples, which may not have the best tissue tropism on nasopharyngeal mucosa (27). BBV154 vaccine used simian Ad36, which was isolated from a nonrespiratory tissue, and the vaccine was delivered by nasal drop rather than intranasal spray (28). We employed human Ad5, initially isolated from the human tonsil, which may have the ideal tissue tropism for the nasopharyngeal tract (15). Despite the vaccination site being in the nasal passage and our primary goal being to stimulate mucosal immunity, especially spike-specific sIgA against BA.1, we could also detect a modest induction of serum-neutralizing antibodies. The 88.9%–100% conversion rate of serum neutralizing antibodies against wild-type, BA.1, and BA.5 was higher than other intranasal vaccines reported thus far. We found that the elevation and titer of serum neutralizing titers were biased toward wild-type after the first dose of intranasal vaccination, likely due to the immune imprinting effect from the previously injected wild-type vaccines. However, the second dose of the Omicron vaccine could overcome the imprinting effect on serum antibodies. In contrast, nasal mucosal spike-specific sIgA elevation was comparable between wild-type and BA.1, without apparent influence from previously injected wild-type vaccines. These results suggested that the nasal mucosal and systemic immune responses are somewhat compartmentalized. Therefore, assessing nasal mucosal sIgA is a more relevant immunological correlate than serum antibodies for nasal vaccines. Preexisting immunity against adenovirus is one concern in repeated usage of adenoviruses, especially adenoviruses with high seroprevalence as vaccine vectors. Previous clinical studies using an Ad5-vectored influenza vaccine suggested that intranasal vaccinations were effective in the presence of preexisting anti-Ad5 immunity (29). In our study, the nasal spike-specific sIgA showed a greater elevation (average 10-fold) between the first and second doses. Thus, the second dose remained effective even in the presence of presumably the anti-Ad5 immunity induced by the first dose. We speculate that the presence of limited anti-Ad5 immunity in the nasal passage was insufficient to completely block the influx of a large bolus of Ad5 vaccine. We may thus call each intranasal influx of a large bolus of Ad5 vaccine a “breakthrough vaccination.” In addition to adenoviruses for COVID-19 vaccines, other viral vectors, such as an LAIV carrying RBD, have been used for intranasal vaccination. In a clinical study (23), 12%–18% positive conversion of RBD-specific IgA in nasopharyngeal swab samples and 10%–22% seroconversion of RBD-specific IgG was observed, but no results on serum neutralization were reported. This vaccine showed 28.2% effectiveness against Omicron infection in people aged 18–59 but has not been tested in children. FluMist, an intranasal seasonal influenza vaccine based on cold-adapted LAIV, is more efficacious than intramuscularly injected vaccines for protecting children (30). LAIV induced a weak serum antibody response but more elevation of mucosal IgA and conferred comparable protection to the intramuscularly injected vaccine in adults (31). So far, we have tested this Ad5-vectored intranasal vaccine only in adults. Future studies should address the immunogenicity and protection effectiveness of different intranasal vaccines in children, adults, and people who are aged. We propose that using different viruses as a vaccine vector; viruses of different serotypes or species of origin; and different antigen selection (RBD or spike), antigen gene design and optimization, expression cassette, formulation, and method of administration (such as intranasal spraying or dropping) may contribute to different immunological outcome and protection efficacy. The hallmark of our intranasal vaccine was the induction of broad-spectrum spike-specific sIgA in the nasal passage. Although this study did not evaluate the neutralization titers in NMLFs because of the constraint of sample collection, earlier studies by our team and other investigators have shown that nasal IgA in NMLFs possesses neutralizing activities against SARS-CoV-2 (17, 32, 33). It has been established that the risk of breakthrough infection was lower in convalescents with higher levels of nasal or salivary spike-specific sIgA (6, 7). In another study, we purified paired nasal sIgA, serum IgG, and IgA from NMLFs and serum samples and compared their neutralizing activities against both pre-Omicron strains and Omicron subvariants (34). Nasal sIgA can be over 100-fold more potent than serum IgG and IgA in neutralizing Omicron subvariants, including XBB and JN.1. The primary objective of this study was to evaluate the safety and immunogenicity of intranasal vaccination, which was not designed to assess protection efficacy. The zero-COVID policy was lifted when this study began. Many participants were infected before the vaccination could induce sufficient immune barrier to counter infection, and these infected participants had to drop out of the study. We observed that 43 out of 75 participants (57.3%) were infected days 15–28 after the first dose, December 14–30, 2022, suggesting that 1 dose with 4.5-fold induction of nasal spike-specific sIgA was not sufficient to block infection in an extremely high–viral load environment. Interestingly, 29 participants who received the second dose December 28–30, 2022, whose nasal spike-specific sIgA elevated 51.5-fold, reported no infection in the following 3 months, demonstrating that the second dose is critical for preventing at least symptomatic infection. In the same period, the accumulated infection rate in the population increased from less than 1% on December 7, 2022, to over 85% on January 18, 2023, according to a public announcement by the Guangzhou Municipal Health Commission (19). A report based on detecting SARS-CoV-2 ORF8 seroconversion also showed that the infection attack ratio was over 80.7% for samples collected January 5–14, 2023 (18). The limitation of this study in assessing protection effectiveness was the lack of a placebo group to monitor the infection rate with the exact timing as the intranasally vaccinated group, which may have an impact given the dynamic epidemic curve between the first and second doses administered. The exclusion of infected participants also lessened the study population. Nevertheless, we believe that the 2-dose regimen is more effective than 1 dose in preventing infection: 1) there was a time overlap between people who received the first dose and the second dose (December 28–30, 2022); 2) except for 2 participants who were infected on days 1 and 3 after the second dose, no more infections were reported as the nasal spike-specific sIgA elevated to 51-fold over the baseline; 3) according to a China CDC report (35), the infection rate based on PCR test started to increase on December 8, 2022; peaked on December 25, 2022, at 29.2%; and then decreased gradually but still was 5.5% on January 23, 2023. When participants received the second dose December 28–30, 2022, the infection rate in the population was at a high level. In particular, these participants were health care workers who worked in a respiratory disease hospital, where many patients with COVID-19 came in for medical care. Therefore, they were constantly exposed to a high–viral load environment. A randomized, placebo-controlled clinical study should be conducted in the future to obtain a more conclusive result. As the level of nasal spike-specific sIgA decreases over time, the chance of infection may increase. We found that nasal spike-specific sIgA decreased to 18.2-fold over baseline 3 months after the second dose but was still much higher than 4.5-fold after the first dose, keeping these people uninfected. Concurrent with a report that nasal sIgA wanes to the baseline level in 9 months after natural infection (20), our finding that intranasal vaccination–induced spike-specific sIgA descended to 35% of its peak level after 3 months suggests that an intranasal booster may be needed every 6–9 months to maintain effective protection against infection. We tried stratifying the nasal sIgA and serum antibodies between uninfected and infected participants (Supplemental Figure 2). On day 14 after the first dose, the mean GMFI of nasal sIgA for BA.1+L452R (BA.5-like) was 8.0 versus 4.5 between infected and uninfected on days 15–28, whereas the mean GMFI of serum neutralization for BA.5 was 8.3 versus 4.2. Both nasal sIgA and serum neutralization showed a trend of greater induction (nearly 2-fold) among uninfected participants but lack of statistical significance, probably due to relatively small sample size and short observation duration (14–28 days after the first dose) because the second dose was initiated on day 28. On day 14 after the second dose, the mean GMFI of nasal sIgA for BA.1+L452R (BA.5-like) had an 11.5-fold increase from 1:5.6 to 1:64.5. In contrast, serum neutralizing GMFI for BA.5 had only a 3.1-fold increase from 1:5.5 to 1:16.8. Serum neutralizing titer for BA.5 had only a 3.4-fold increase from 1:89 to 1:303, which was lower than intramuscularly injected vaccines that can elicit much higher serum neutralizing titer but still had Omicron breakthrough infections. Intramuscularly injected vaccines can elicit much higher serum neutralizing titer but are limited in preventing Omicron breakthrough infections. Given that accumulated evidence showed that the level of nasal spike-specific sIgA is inversely correlated with the risk of SARS-CoV-2 Omicron infection, we believe that the dramatic induction of nasal spike-specific sIgA after intranasal booster is the key contributor to the defense against infection through the airway. In conclusion, this study demonstrated that a 2-dose intranasal vaccination regimen using NB2155 can induce spike-specific sIgA in the nasal mucosa and potentially contribute to protection against Omicron infection. Further clinical studies should be conducted to develop a safe, effective, and user-friendly vaccine for preventing infections and blocking virus transmission in the population.

A fentanyl vaccine developed by researchers at the University of Houston is expected to head to clinical trials sometime in the middle of next year, with the hope of being a groundbreaking solution to a deadly crisis.

Nipocalimab showed a significant decrease in Clinical European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index.

Le 24 mai, des chercheurs chinois ont annoncé avoir transplanté avec succès un foie de porc génétiquement modifié sur un patient humain vivant atteint d’un cancer du foie.

A l'Institut de recherche sur les dispositifs médicaux de Suzhou de l'Université du Sud-Est, situé à Suzhou, dans la province chinoise du Jiangsu (est), on a...

SignificanceRespiratory virus infections in humans are a significant global health concern, causing a wide range of diseases with substantial morbidity and mortality worldwide. This underscores the...