Waning Effectiveness of SARS-CoV-2 mRNA Vaccines in Older Adults: A Rapid Review

The U.S. Centers for Disease Control and Prevention (CDC) and other health agencies have recently recommended a booster dose of COVID-19 vaccines for specific vulnerable groups including adults 65 years and older. There is limited evidence whether vaccine effectiveness in older adults decreases over time, especially against severe COVID-19. We performed a rapid review of published studies available through 04 November 2021 that provide effectiveness data on mRNA vaccines approved/licensed in the United States and identified eight eligible studies which evaluated vaccine effectiveness in older adults. There is evidence of a decline in vaccine effectiveness against both SARS-CoV-2 infection and severe COVID-19 in older adults among studies which analyzed data up to July-October 2021. Our findings suggest that vaccine effectiveness diminishes in older adults, which supports the current recommendation for a booster dose in this population.

Duration of immunity against COVID-19 after vaccination in Indian subcontinent

Coronavirus disease (COVID-19) continues to be a major health concern leading to substantial mortality and morbidity across the world. Vaccination is effective in reducing the severity and associated mortality. Data pertaining to the duration of immunity, antibody waning and the optimal timing of booster dose administration is limited. In this cross-sectional study, we assessed the antibody levels in healthcare workers who were fully vaccinated after obtaining Institutional ethics committee approval and informed consent. Whole blood was collected and enumeration of S1/S2 neutralizing antibody levels was carried out using LIAISON SARS-COV-2 S1/S2 IgG assay. A total of 1636 individuals who were vaccinated with Covaxin or Covishield were included. Of these, 52% were males with a median age of 29 years. Diabetes and Hypertension was noted in 2.32% (38/1636) and 2.87% (47/1636) of the individuals. Spike neutralizing antibodies were below the detectable range (<15 AU/ml) in 6.0% (98/1636) of the individuals. Decline in neutralizing antibody was seen in 30% of the individuals above 40 years of age with comorbidities (diabetes and hypertension) after 6 months. These individuals may be prioritized for a booster dose at 6 months.

SARS-CoV-2 Omicron Neutralization After Heterologous Vaccine Boosting

As part of an ongoing study assessing homologous and heterologous booster vaccines, following primary EUA series, we assessed neutralization of D614G and Omicron variants prior to and 28 days after boost. Subset analysis was done in six combinations (N = 10/group): four homologous primary-booster combinations included mRNA-1273 two-dose priming followed by boosting with 100-μg or 50-μg mRNA-1273, Ad26.COV2.S single-dose priming followed by Ad26.COV2.S booster and BNT162b2 two-dose priming followed by BNT162b2 boosting; and two heterologous primary-booster combinations: BNT162b2 followed by Ad26.COV2.S and Ad26.COV2.S followed by BNT162b2. Neutralizing antibody (Nab) titers to D614G on the day of boost (baseline) were detected in 85-100% of participants, with geometric mean titers (GMT) of 71-343 in participants who received an mRNA vaccine series versus GMTs of 35-41 in participants primed with Ad26.OV2.S. Baseline NAb titers to Omicron were detected in 50-90% of participants who received an mRNA vaccine series (GMT range 12.8-24.5) versus 20-25% among participants primed with Ad26.COV2.S. The booster dose increased the neutralizing GMT in most combinations to above 1000 for D614G and above 250 for Omicron by Day 29. Homologous prime-boost Ad26.COV2.S had the lowest NAb on Day 29 (D614G GMT 128 and Omicron GMT 45). Results were similar between age groups. Most homologous and heterologous boost combinations examined will increase humoral immunity to the Omicron variant.

Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients: the Italian VAX4FRAIL study

Background: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. Methods: We designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. Results: Overall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. Conclusions: Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

Persistence of immunity and impact of a third (booster) dose of an inactivated SARS-CoV-2 vaccine, BBV152; a phase 2, double-blind, randomised controlled trial

Background: Neutralising antibody responses to SARS-CoV-2 vaccines have been reported to decline within 6 months of vaccination, particularly against Variants of Concern (VOC). We assessed the immunogenicity and safety of a booster dose of BBV152 administered 6 months after the second of a two-dose primary vaccination series. Methods: In an ongoing phase 2 trial (ClinicalTrials.gov: NCT04471519) the protocol was amended after six months to re-consent and randomise 184 previously vaccinated participants to receive a third dose of vaccine or placebo on Day 215. The primary outcome was to measure neutralising antibody titres by plaque-reduction neutralisation test (PRNT50) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome. Findings: Four weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197.0 PRNT50 (95% CI: 155.6,249.4); this level declined to 23.9 PRNT50 (14.0,40.6) six months later, with a seroconversion rate of 75.4% (95% CI: 68.4,81.6). Four weeks after booster vaccination the GMT increased on Day 243 to 746.6 PRNT50 (514.9,1081) compared with 100.7 PRNT50 (43.6,232.6) in the placebo group. Corresponding seroconversion rates were 98.7% (92.8,99.9) and 79.8% (69.6,87.8). Increased titres in the placebo group were attributed to natural infection as the study was conducted during the second wave of COVID-19 in India. PRNT50 titres against the SARS-CoV-2 variants increased Alpha (32.6 fold), Beta (161.0 fold), Delta (264.7 fold), and Delta plus (174.2 fold) after the booster vaccination. We found that vaccine induces both memory B and T cells with a distinct AIM+ specific CD4+T central and effector memory phenotype, including CD8+ TEMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported. Interpretation: Six months after a two dose BBV152 vaccination series cell mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19 to 97 fold after a third vaccination. Booster BBV152 vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections.

Polyphenols in Matily Herbal & Spices Boosts Antibodies in an Elderly Following COVID 19 Infections – A Case Study

An elderly patient had COVID-19 infection in August 2020 and started the home remedies treatment for the first 18 hours, followed by Azithromycin 250 mg for 6 days. The patient revered well, and the infection was confirmed by antibodies in the patient's serum. Later on, the patient was on Matily Herbal Drink and Matily Herbal & Spices Mix to avoid complications connected with COVID-19 re-infection. After completing 12 months of post COVID-19 infection, the antibodies were assessed to find the status. It was found to be increased in qualitative assessment. The quantitative assessment of antibodies showed a much higher value compared with individuals who had both the dose of vaccines and tested the blood after two weeks since the second dose of vaccine. We suggest that the increased antibodies could be because of the bioavailability of polyphenols present in the Matily Herbal Drink and Matily Herbal & Spices Mix. Polyphenols inactivate COVID-19 virus and this may have helped the body to increase its antibody production. The bioavailability of polyphenols depends on various factors, including acidulants in the diet. Based on the present studies, we suggest India should have her own strategies to increase antibodies in the population instead of just following the norms laid by International Agencies for the booster dose of vaccine Keywords: COVID-19, Matily Herbal Drink, Matily Herbal, Spices Mix

Safety and Immunogenicity of the Third Booster Dose with Inactivated, Viral Vector, and mRNA COVID-19 Vaccines in Fully Immunized Healthy Adults with Inactivated Vaccine

The coronavirus disease 2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2), in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7–alpha, B.1.351–beta, and B.1.617.2–delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of IFN-ɣ secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.

Cell-mediated and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients

Importance: Data on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited. Objective: To determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response. Design: Retrospective observational cohort study. Setting: Large healthcare system in Northern California. Participants: This study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection. Exposure(s): Immunosuppressive diseases and therapies. Main Outcome(s) and Measure(s): Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination. Results: 496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (n=48, P<.001), sphingosine 1-phsophate (S1P) receptor modulators (n=11, P<.001), mycophenolate (n=78, P=.002), and B cell lymphoma (n=55, P=.004); those associated with low rates of cellular response included S1P receptor modulators (n=11, P<.001) and mycophenolate (n=69, P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose. Conclusions and Relevance: Cellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.

Sequential immunization with SARS-CoV-2 RBD vaccine induces potent and broad neutralization against variants in mice

The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

Comparison of infectious SARS-CoV-2 from the nasopharynx of vaccinated and unvaccinated individuals

The frequency of SARS-CoV-2 breakthrough infections in fully vaccinated individuals increased with the emergence of the Delta variant, particularly with longer time from vaccine completion. However, whether breakthrough infections lead to onward transmission remains unclear. Here, we conducted a study involving 125 patients comprised of 72 vaccinated and 53 unvaccinated individuals, to assess the levels of infectious virus in in vaccinated and unvaccinated individuals. Quantitative plaque assays showed no significant differences in the titers of virus between these cohorts. However, the proportion of nasopharyngeal samples with culturable virus was lower in the vaccinated patients relative to unvaccinated patients (21% vs. 40%). Finally, time-to-event analysis with Kaplan-Myer curves revealed that protection from culturable infectious virus waned significantly starting at 5 months after completing a 2-dose regimen of mRNA vaccines. These results have important implications in timing of booster dose to prevent onward transmission from breakthrough cases.