ABSTRACT
Waning immunity to vaccination represents a major challenge in vaccinology. Whether booster vaccination improves the durability of immune responses is unknown. Here we show, using a cohort of 55 adult vaccinees who received the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine against SARS-CoV-2, that a booster (i.e., 3rd immunization) dose at 6 - 10 months increased the half-life of serum neutralizing antibody (nAb) titers to 76 days from 56 - 66 days estimated after the primary two-dose vaccination series. A second booster dose (i.e., 4th immunization) more than a year after the primary vaccination increased the half-life further to 88 days. However, despite this modestly improved durability in nAb responses against the Wuhan strain, there was a loss in neutralization capacity against Omicron subvariants, especially the recently emerged variants, BA.2.75.2 and BQ.1.1 (35 and 50-fold drop in titers respectively, relative to the ancestral (WA.1) strain. While only 55 - 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (3rd dose), the response declined to below the detection limit in almost all individuals by 6 months. Notably, even against BA.1 and BA.5, the titers declined rapidly in a third of the vaccinees and were below the detection limit at 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months. Collectively, our data show that the durability of immune responses improves following subsequent booster immunizations; however, the emergence of immune evasive variants reduces the effectiveness of booster doses in preventing infection.
ABSTRACT
Despite the remarkable efficacy of COVID-19 vaccines, waning immunity, and the emergence of SARS-CoV-2 variants such as Omicron represents a major global health challenge. Here we present data from a study in non-human primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine, consisting of RBD (receptor binding domain) on the I53-50 nanoparticle, adjuvanted with AS03, currently in Phase 3 clinical trial (NCT05007951). Vaccination induced robust neutralizing antibody (nAb) titers that were maintained at high levels for at least one year after two doses (Pseudovirus nAb GMT: 2207, Live-virus nAb GMT: 1964) against the ancestral strain, but not against Omicron. However, a booster dose at 6-12 months with RBD-Wu or RBD-{beta} (RBD from the Beta variant) displayed on I53-50 elicited equivalent and remarkably high neutralizing titers against the ancestral as well as the Omicron variant. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Importantly, vaccination resulted in protection against Omicron infection in the lung (no detectable virus in any animal) and profound suppression of viral burden in the nares (median peak viral load of 7567 as opposed to 1.3x107 copies in unvaccinated animals) at 6 weeks post final booster. Even at 6 months post vaccination, there was significant protection in the lung (with 7 out of 11 animals showing no viral load, 3 out of 11 animals showing ~20-fold lower viral load than unvaccinated controls) and rapid control of virus in the nares. These results highlight the durable cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine platform.
ABSTRACT
Effects of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) on synaptic transmission were investigated on neurons in substantia gelatinosa (SG) of the spinal dorsal horn by whole-cell voltage clamp recording. Both EM-1 (1 μmol/L) and EM-2 (1 μmol/L)remarkably reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). These effects were antagonized by 3-funaltrexamine ( β-FNA, 10 μmol/L), a selective μ-opioid receptor antagonist. Noticeably, EM-1 showed higher potency in decreasing the frequency of mEPSCs and mIPSCs than that of EM-2. These results indicate that EMs suppress both excitatory and inhibitory synaptic transmission by activating presynaptic μ-opioid receptors in the SG and EM-1, compared with EM-2, might be a more potent endogenous analgesic at the spinal cord level.
