The immune response to inactivated influenza vaccines (IIV) is influenced by multiple factors, including hemagglutinin content and egg-based manufacturing. Only two US-licensed vaccines are manufactured without egg passage: cell culture-based inactivated vaccine (ccIIV) and recombinant vaccine (RIV). We conducted a randomized open-label trial in central Wisconsin during the 2018-19 and 2019-20 seasons to compare immunogenicity of sequential vaccination. Participants 18-64 years old were randomized 1:1:1 to receive RIV, ccIIV or IIV in strata defined by number of influenza vaccine doses in the prior 3 years. They were revaccinated with the same product in year two. Paired serum samples were tested by hemagglutination inhibition against egg-adapted and cell-grown vaccine viruses. Serologic endpoints included geometric mean titer (GMT), mean fold rise, and percent seroconversion. There were 373 participants randomized and vaccinated in 2018-19; 332 were revaccinated in 2019-20. In 2018-19, RIV and ccIIV were not more immunogenic than IIV against A/H1N1. The post-vaccination GMT against the cell-grown 3C.2a A/H3N2 vaccine virus was higher for RIV vs IIV (p = .001) and RIV vs ccIIV (p = .001). The antibody response to influenza B viruses was similar across study arms. In 2019-20, GMT against the cell-grown 3C.3a A/H3N2 vaccine virus was higher for RIV vs IIV (p = .03) and for RIV vs ccIIV (p = .001). RIV revaccination generated significantly greater backboosting to the antigenically distinct 3C.2a A/H3N2 virus (2018-19 vaccine strain) compared to ccIIV or IIV. This study adds to the evidence that RIV elicits a superior immunologic response against A/H3N2 viruses compared to other licensed influenza vaccine products.

A crucial step in lowering the risk of invasive pneumococcal illness in high-risk populations, such as individuals with plaque psoriasis, is pneumococcal vaccination. The serologic response to the sequential vaccination with Prevenar 13 (PCV13) and Pneumovax 23 (PPSV23) in psoriasis patients under immunosuppressive therapy is still poorly characterized despite national recommendations suggesting vaccination for immunocompromised patients. In this prospective study, we investigated the serological response in 57 patients under active systemic treatment for moderate to severe plaque psoriasis who underwent sequential vaccination with PCV13 followed by PPSV23. Our analysis focused on global and serotype-specific anti-pneumococcal antibody responses over a 7-month period post-vaccination. Our findings reveal a robust serological response in patients with plaque psoriasis under systemic therapy. When comparing our results with a cohort of kidney transplant recipients who completed a similar sequential vaccination protocol, psoriasis patients showed higher antibody concentrations. In psoriasis patients, the mean levels of all global antibody classes tested (IgG, IgG2, IgA, IgM) increased more than 4-fold (P < 0.0001) and serotype-specific antibodies more than 1.9-fold (P < 0.01). In addition to providing strong evidence of the safety and effectiveness of sequential pneumococcal vaccination in individuals with plaque psoriasis, our work sheds light on the complex interactions that exist between immunosuppressive treatment, vaccination schedule, and antibody responses in various risk groups.
OBJECTIVE: To protect against severe courses of infection with Streptococcus pneumoniae, the national guidelines recommend sequential vaccination for these patients. However, there are only studies on the efficacy of a single administration of these vaccines in this particular risk group. The immunological responses to the vaccine were correlated with clinical patient data. In summary, our study shows for the first time that sequential vaccination is immunogenic in patients with moderate to severe plaque psoriasis.

In Italy, a sequential pneumococcal vaccination with conjugate vaccine (PCV) and polysaccharide vaccine (PPSV23) is recommended for individuals aged ≥ 65 years and those at risk for pneumococcal disease (PD) aged ≥ 6 years. The aim of this study was to assess the cost-effectiveness of the new vaccines, i.e., approved 15-valent and 20-valent PCVs. A published Markov model was adapted to evaluate the lifetime cost-effectiveness of vaccination with PCV15 + PPSV23 versus PCV13 + PPSV23, PCV20 alone, PCV20 + PPSV23, and No Vaccination. Simulated cohorts representing the Italian population, including individuals aged ≥ 65 years, those at risk aged 50-100 years, and those deemed high risk aged 18-100 years were assessed. Outcomes were accrued in terms of incremental PD cases, costs, quality-adjusted life years, life years, and the cost-utility ratio relative to PCV13 + PPSV23. The conservative base case analysis, including vaccine efficacy based on PCV13 data, showed that sequential vaccination with PCV15 or PCV20 in combination with PPSV23 is preferred over sequential vaccination with PCV13 + PPSV23. Especially in the high-risk group, PCV15 + PPSV23 sequential vaccination was dominant over No Vaccination and resulted in an ICUR of €3605 per QALY gained. Including PCV20 + PPSV23 into the comparison resulted in the domination of the PCV15 + PPSV23 and No Vaccination strategies. Additionally, explorative analysis, including the geometric mean titer (GMT) informed vaccine effectiveness (VE) was performed. In the low-risk and high-risk groups, the results of the GMT scenarios showed PCV15 + PPSV23 to be dominant over the other sequential vaccines. These findings suggest that if real-world studies would confirm a difference in vaccine effectiveness of PCV15 and PCV20 versus PCV13 based on GMT ratios, PCV15 + PPSV23 could prove a highly immunogenic and effective vaccination regime for the Italian adult population.

OBJECTIVE: Vaccination against Streptococcus pneumoniae is recommended in transplant recipients to reduce the morbidity and mortality from invasive pneumococcal disease. Previous studies indicate that transplant recipients can produce specific antibodies after vaccination with the 13-valent pneumococcal conjugate vaccine Prevenar 13 (PCV13) or the pneumococcal polysaccharide vaccine Pneumovax 23 (PPSV23). National guidelines recommend sequential vaccination with PCV13 followed by PPSV23 in kidney transplant patients. However, there are currently no data on the serological response in kidney transplant recipients, who received a sequential vaccination with PCV13 and PPSV23.
METHODS: In the current study, we sequentially vaccinated 46 kidney transplant recipients with PCV13 and PPSV23 and determined global and serotype-specific anti-pneumococcal antibody responses in the year following vaccination.
RESULTS: Serotype-specific and global anti-pneumococcal antibody concentrations were significantly higher compared to baseline. We observed that serotype-specific antibody responses varied by serotype (between 2.2- and 2.9-fold increase after 12 months). The strongest responses after 12 months were detected against the serotypes 9N (2.9-fold increase) and 14 (2.8-fold increase). Global antibody responses also varied with respect to immunoglobulin class. IgG2 revealed the highest increase (2.7-fold), IgM the lowest (1.7-fold). Sequential vaccination with both vaccines achieved higher antibody levels in comparison with a historical cohort studied at our institute, that was vaccinated with PCV13 alone. During the 12-months follow-up period, none of the patients developed pneumococcal-associated pneumonia or vaccination-related allograft rejection.
CONCLUSIONS: In conclusion, we strongly recommend sequential vaccination over single immunization in kidney transplant recipients.

To effectively prevent and control the COVID-19 pandemic, countries have adopted a booster vaccination strategy. This study aimed to estimate the cost-effectiveness of sequential booster COVID-19 vaccination compared to two-dose inactivated vaccination in China from a societal perspective. A Markov model was developed to estimate the cost-effectiveness of sequential vaccination, including two doses of an inactivated vaccine followed by a booster shot of an inactivated vaccine, adenovirus vectored vaccine, protein subunit vaccine, or mRNA vaccine. The incremental effects of a booster shot with an inactivated vaccine, protein subunit vaccine, adenovirus vectored vaccine, and mRNA vaccine were 0.0075, 0.0110, 0.0208, and 0.0249 QALYs and saved costs of US$163.96, US$261.73, US$583.21, and US$724.49, respectively. Under the Omicron virus pandemic, the sequential vaccination among adults and the elderly (aged 60-69, 70-79, over 80) was consistently cost-saving, and a booster shot of the mRNA vaccine was more cost-saving. The results indicate that the sequential vaccination strategy is cost-effective in addressing the COVID-19 pandemic, and improving vaccination coverage among the elderly is of great importance in avoiding severe cases and deaths.

Although COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging on development of multispecies coronavirus vaccines. Here we develop prototype lipid nanoparticle (LNP)-mRNA vaccine candidates against SARS-CoV-2 Delta, SARS-CoV, and MERS-CoV, and we test how multiplexing LNP-mRNAs can induce effective immune responses in animal models. Triplex and duplex LNP-mRNA vaccinations induce antigen-specific antibody responses against SARS-CoV-2, SARS-CoV, and MERS-CoV. Single-cell RNA sequencing profiles the global systemic immune repertoires and respective transcriptome signatures of vaccinated animals, revealing a systemic increase in activated B cells and differential gene expression across major adaptive immune cells. Sequential vaccination shows potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrate the feasibility, antibody responses, and single-cell immune profiles of multispecies coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights into optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species.

In organ transplant recipients, the rate of invasive pneumococcal diseases is 25 times greater than in the general population. Vaccination against S. pneumoniae is recommended in this cohort because it reduces the incidence of this severe form of pneumococcal infection. Previous studies indicate that transplant recipients can produce specific antibodies after pneumococcal vaccination. However, it remains unclear if vaccination also induces specific cellular immunity. In the current study on 38 kidney transplant recipients, we established an interferon-γ ELISpot assay that can detect serotype-specific cellular responses against S. pneumoniae. The results indicate that sequential vaccination with the conjugated vaccine Prevenar 13 and the polysaccharide vaccine Pneumovax 23 led to an increase of serotype-specific cellular immunity. We observed the strongest responses against the serotypes 9N and 14, which are both components of Pneumovax 23. Cellular responses against S. pneumoniae correlated positively with specific IgG antibodies (r = 0.32, p = 0.12). In conclusion, this is the first report indicating that kidney transplant recipients can mount specific cellular responses after pneumococcal vaccination. The ELISpot we established will allow for further investigations. These could help to define, for example, factors influencing specific cellular immunity in immunocompromised cohorts or the duration of cellular immunity after vaccination.

BACKGROUND: Despite use of the 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) over the last decade, the disease burden of pneumococcal pneumonia is still high. We evaluated the field effectiveness of PCV13, PPSV23, and sequential vaccination against pneumococcal pneumonia in older adults.
METHODS: This prospective multicenter study was conducted in adults aged ≥ 65 years with hospitalized community-acquired pneumonia (CAP) between September 2015 and August 2017. The case-control test-negative design was used to estimate vaccine effectiveness (VE) against pneumococcal CAP.
RESULTS: Of 1,525 cases with hospitalized CAP, 167 (11.0%) were identified as pneumococcal CAP. In the elderly aged ≥65 years, the adjusted VE of pneumococcal vaccines against pneumococcal CAP was statistically insignificant: 40.0% (95% CI -10.8% to 67.5%) for PCV13 and 11.0% (95% CI, -26.4% to 37.3%) for PPSV23. However, in the younger subgroup (aged 65-74 years), sequential PCV13/PPSV23 vaccination showed the highest adjusted VE of 80.3% (95% CI 15.9% to 95.4%), followed by single-dose PCV13 (adjusted VE 66.4%; 95% CI 0.8% to 88.6%) and PPSV23 (adjusted VE 18.5%; 95% CI -38.6% to 52.0%).
CONCLUSIONS: Sequential PCV13/PPSV23 vaccination is most effective for preventing pneumococcal CAP among the elderly aged 65-74 years.

Streptococcus pneumoniae causes pneumococcal disease, and older adults are at an increased risk. Sequential vaccination of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for broad protection against pneumococcal disease in some countries.
This phase III trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 12 months later by PPSV23, in healthy adults aged ≥50 years (NCT03480763). A total of 652 participants were randomized 1:1 to receive either V114 or PCV13, followed by PPSV23.
The most common solicited adverse events (AEs) following PCV vaccination included injection-site pain and fatigue. Higher proportions of participants with these events were observed in the V114 group following PCV; however, these differences were not clinically significant. Following PPSV23 vaccination, the most common solicited AEs were injection-site pain and injection-site swelling; the proportions of participants with these events were comparable between both groups. Incidence of serious AEs was low in both groups following PCV and PPSV23, and none were related to study vaccines. No deaths occurred during the study. Serum opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations were comparable between both groups for all 15 serotypes in V114 following PPSV23. Immune responses elicited by V114 persisted for at least 12 months. Immune responses at 30 days and 12 months post-vaccination with PCV were comparable between both groups for the 13 shared serotypes and higher in the V114 group for the V114-unique serotypes (22F and 33F).
Administration of V114 followed by PPSV23 was well tolerated and induced comparable antibody levels to PCV13 followed by PPSV23 in healthy adults aged ≥50 years.

Introduction: Immunogenicity studies evaluating sequential administration of pneumococcal conjugate vaccine (PCV) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) or revaccination with PPSV23 have raised concerns that PPSV23 may not elicit higher antibody levels than those measured following PCV or first PPSV23 dose.Areas covered: Recent literature was evaluated for evidence of blunted immune response (hyporesponsiveness), focusing on studies using adequate intervals between doses in accordance with vaccination recommendations. In eight of nine studies that evaluated revaccination with PPSV23 at an interval of ≥5 years after the previous dose, immunoglobulin G geometric mean concentrations and/or opsonophagocytic assay geometric mean titers for most serotypes increased from pre- to post-repeat vaccination and were comparable between repeat and primary vaccination groups post-vaccination. In seven studies in which PPSV23 was administered after PCVs (8 weeks to 1 year apart), responses to PPSV23 were comparable to those seen after initial PCV dose for shared vaccine serotypes. Studies in which PCVs were administered after PPSV23 were not evaluated.Expert opinion: Published data suggest immune responses following repeat vaccination with PPSV23, or sequential PCV/PPSV23 vaccination, are robust, without evidence of hyporesponsiveness. PPSV23 vaccination of at-risk adults is essential to ensure broad protection against all 23 vaccine serotypes.