Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals.

In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern. Modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as Imvamune, JYNNEOS or Imvanex) is a third-generation smallpox vaccine that is authorized and in use as a vaccine against MPX. To date, there are no data showing MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals nor vaccine efficacy against MPX. Here we show that MPXV-neutralizing antibodies can be detected after MPXV infection and after historic smallpox vaccination. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies. Dose-sparing of an MVA-based influenza vaccine leads to lower MPXV-neutralizing antibody levels, whereas a third vaccination with the same MVA-based vaccine significantly boosts the antibody response. As the role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility is currently unclear, we conclude that cohort studies following vaccinated individuals are necessary to assess vaccine efficacy in at-risk populations.

Humoral and cellular immune responses after COVID-19 vaccination of lung transplant recipients and patients on the waiting list: a 6-month follow-up.

Background: Data on cellular response and the decay of antibodies and T cells in time are scarce in lung transplant recipients (LTRs). Additionally, the development and durability of humoral and cellular immune responses have not been investigated in patients on the waitlist for lung transplantation (WLs). Here, we report our 6-month follow-up of humoral and cellular immune responses of LTRs and WLs, compared with controls. Methods: Humoral responses to two doses of the mRNA-1273 vaccination were assessed by determining spike (S)-specific IgG antibodies and neutralizing antibodies. Cellular responses were investigated by interferon gamma (IFN-γ) release assay (IGRA) and IFN-γ ELISpot assay at 28 days and 6 months after the second vaccination. Results: In LTRs, the level of antibodies and T-cell responses was significantly lower at 28 days after the second vaccination. Also, WLs had lower antibody titers and lower T-cell responses compared with controls. Six months after the second vaccination, all groups showed a decrease in antibody titers and T-cell responses. In WLs, the rate of decline of neutralizing antibodies and T-cell responses was significantly higher than in controls. Conclusion: Our results show that humoral and cellular responses in LTRs, if they develop, decrease at rates comparable with controls. In contrast, the inferior cellular responses and the rapid decay of both humoral and cellular responses in the WL groups imply that WLs may not be protected adequately by two vaccinations and repeat boostering may be necessary to induce protection that lasts beyond the months immediately post-transplantation.

High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.

BACKGROUND: Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression. METHODS: The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load. RESULTS: Humoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation. CONCLUSIONS: This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response.

Divergent SARS-CoV-2 Omicron-reactive T and B cell responses in COVID-19 vaccine recipients.

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T cell responses targeting SARS-CoV-2 D614G [wild type (WT)] and the Beta, Delta, and Omicron variants of concern in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273, or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which substantially decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent. BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV2 priming partially restored neutralization of the Omicron variant, but responses were still up to 17-fold decreased compared with WT. SARS-CoV-2-specific T cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4+ than CD8+ T cells. No significant differences were detected between WT- and variant-specific CD4+ or CD8+ T cell responses, including Omicron, indicating minimal escape at the T cell level. This study shows that vaccinated individuals retain T cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.

Measles seroprevalence among Dutch travelling families.

BACKGROUND: While measles vaccination is widely implemented in national immunisation programmes, measles incidence rates are increasing worldwide. Dutch inhabitants who were born between 1965-1975 may have fallen between two stools, lacking protection from a natural infection, and having missed the introduction of the measles vaccination schedule. With this study we aim to find the measles seroprevalence in travellers born between 1965 and 1975, compared to those born before 1965 and after 1975. METHODS: Families travelling to Eastern Europe or outside Europe during the preceding year were recruited via Dutch secondary schools between 2016 and 2018. Their vaccination status was assessed using questionnaires, vaccination records and measles serology in dried blood spot (DBS) eluates. Measles virus antibody concentrations were determined with an ELISA (EUROIMMUNE®) and a subset was retested with a focus reduction neutralization assay (FRNT). RESULTS: In 188 (79%) of the 239 available DBS eluates, the ELISA could detect sufficient measles virus-specific IgG antibodies. Of the negative samples that were retested with FRNT, 85% remained negative, resulting in an overall seroprevalence of 82% [95% CI 76-86]. Children had a lower seroprevalence (72%) than adults (87%). Travellers born between 1965 and 1975 were protected in 89%. CONCLUSIONS: In this study, we report a measles seroprevalence of 82% among Dutch travelling families. Remarkably, seroprevalence rates were lowest in children (12-18 years) instead of travellers born between 1965 and 1975. Although a fraction of people without detectable antibodies may be protected by other immune mechanisms, these data suggest that measles (re)vaccination should be considered for travellers to endemic regions.

Adherence to hepatitis A travel health guidelines: A cross-sectional seroprevalence study in Dutch travelling families - The Dutch travel Vaccination Study (DiVeST).

BACKGROUND: This Dutch travel Vaccination Study (DiVeST) aimed to study adherence or compliance to Dutch travel health guidelines in travelling families and to identify risk groups to provide better advice and protection for international travellers. METHODS: Between 2016 and 2018, family members who travelled to Eastern Europe or outside Europe during the preceding year were recruited via Dutch secondary schools. The vaccination status of the travellers was assessed using questionnaires and vaccination records and hepatitis A virus antibody concentrations in dried blood spot (DBS) eluates. Subgroups of travellers with lower adherence to guidelines were identified. RESULTS: Of the 246 travellers that participated in this study, 155 (63%) travelled to destinations for which the HAV vaccination was recommended. Of these 155 travellers, 56 (36%) said they visited a pre-travel clinic, and 64 of them (41%) showed a valid HAV vaccination in their vaccination records. Of the 145 travellers with available DBS eluates, anti-HAV antibodies were detected in 98 (68%) of them. CONCLUSIONS: We found that adherence to travel health guidelines, in terms of HAV vaccination, was suboptimal. According to our results, specific attention should be paid to children, persons visiting friends and relatives and those who travel relatively short distances.

An evaluation of serological methods to diagnose tick-borne encephalitis from serum and cerebrospinal fluid.

BACKGROUND: Tick-borne encephalitis (TBE) is an infectious disease endemic to large parts of Europe and Asia. Diagnosing TBE often relies on the detection of TBEV-specific antibodies in serum and cerebrospinal fluid (CSF) as viral genome is mostly not detectable once neurological symptoms occur. OBJECTIVES: We evaluated the performance of TBEV IgM and IgG ELISAs in both serum and CSF of confirmed TBEV patients and discuss the role of (CSF) serology in TBEV diagnostics. STUDY DESIGN: For the assay evaluation we collected specimen from confirmed TBEV patients. Assay specificity was assessed using sera from patients with a related flavivirus infection or other acute infection. A selected ELISA assay was used to analyze TBEV-specific antibodies in CSF and to evaluate the use in confirming TBE diagnosis. RESULTS: In this study the overall sensitivity of the IgM TBEV ELISAs was acceptable (94 -100 %). Four out of five IgM ELISA's demonstrated an excellent overall specificity from 94 -100% whereas a low overall specificity was observed for the IgG TBEV ELISAs (30-71%). Intrathecal antibody production against TBEV was demonstrated in a subset of TBE patients. CONCLUSIONS: In four out of five ELISAs, IgM testing in serum and CSF of TBE patients is specific and confirmative. The lack of IgG specificity in all ELISAs emphasizes the need of confirmatory testing by virus neutralisation, depending on the patient's background and the geographic location of exposure to TBEV. A CSF-serum IgG antibody index can support the diagnosis specifically in chronic disease or once IgM has disappeared.

The performance of the Alere HIV combo point-of-care test on stored serum samples; useful for detection of early HIV-1 infections?

INTRODUCTION: The Alere HIV-1/2 Antigen/Antibody Combo point-of-care test is a commercially available 4th-generation rapid test for the diagnosis of HIV infection, including acute infection. We evaluated the sensitivity of this test in samples from patients with acute, recent or chronic HIV-1 infection. METHODS: A validation of the test was performed using 89 HIV-positive serum samples collected in 2008-2016, that were stored at -20°C. Twenty-three samples were only p24-positive (acute infection); 49 samples were antibody-positive and p24-positive (recent infection); 17 samples were only antibody-positive (chronic infection). HIV infection was confirmed by standard-of-care assays and PCR. Samples came from patients attending an outpatient clinic for STDs at the Public Health Department and from patients within the Erasmus Medical Center, Rotterdam, the Netherlands. RESULTS: The overall sensitivity of the test for diagnosing HIV infection based on detection of p24 antigen and/or antibodies was 92% (95% CI 86% to 98%) (82/89). In acute sera with only p24 antigen positivity, the sensitivity of the test decreased to 65% (95% CI 46% to 85%) (15/23). When both antibody and antigen testing were positive, the p24 sensitivity was only 24% (95% CI 12% to 36%) (12/49), but in these sera the final test result was positive in all sera (49/49) due to the positive antibody component. CONCLUSIONS: In a laboratory setting, this test has an overall sensitivity of 92% to detect any stage of HIV-1 infection using sera specimens. It performs relatively well in detecting early HIV and may be beneficial as an initial screening in patients with a recent exposure to HIV. Additional testing in a laboratory setting remains mandatory as a proportion of acute HIV-1 infections are missed with this test.

Elevated EBNA-1 IgG in MS is associated with genetic MS risk variants.

OBJECTIVE: To assess whether MS genetic risk polymorphisms (single nucleotide polymorphism [SNP]) contribute to the enhanced humoral immune response against Epstein-Barr virus (EBV) infection in patients with MS. METHODS: Serum anti-EBV nuclear antigen 1 (EBNA-1) and early antigen D (EA-D) immunoglobulin γ (IgG) levels were quantitatively determined in 668 genotyped patients with MS and 147 healthy controls. Anti-varicella-zoster virus (VZV) IgG levels were used as a highly prevalent, non-MS-associated control herpesvirus. Associations between virus-specific IgG levels and MS risk SNPs were analyzed. RESULTS: IgG levels of EBNA-1, but not EA-D and VZV, were increased in patients with MS compared with healthy controls. Increased EBNA-1 IgG levels were significantly associated with risk alleles of SNP rs2744148 (SOX8), rs11154801 (MYB), rs1843938 (CARD11), and rs7200786 (CLEC16A/CIITA) in an interaction model and a trend toward significance for rs3135388 (HLA-DRB1*1501). In addition, risk alleles of rs694739 (PRDX5/BAD) and rs11581062 (VCAM1) were independently associated and interacted with normal EBNA-1 IgG levels. None of these interactions were associated with EA-D and VZV IgG titers. CONCLUSIONS: Several MS-associated SNPs significantly correlated with differential IgG levels directed to a latent, but not a lytic EBV protein. The data suggest that the aforementioned immune-related genes orchestrate the aberrant EBNA-1 IgG levels.

Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir.

BACKGROUND & AIMS: We aimed to investigate serum hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B virus (HBV) infection during peginterferon (PEG-IFN) and entecavir (ETV) monotherapy. METHODS: HBsAg was quantified (Abbott ARCHITECT) at baseline and during antiviral therapy (weeks 12, 24, 36, 48) in hepatitis B e antigen (HBeAg-) positive patients treated with ETV (n=33) or PEG-IFN (n=61) and in HBeAg-negative patients treated with ETV (n=37) or PEG-IFN (n=69). RESULTS: Within the HBeAg-positive population, patients treated with PEG-IFN tended to have a steeper HBsAg decline than ETV-treated patients (mean decline 0.94 versus 0.38 log IU/ml at week 48, p=0.07 for comparison of the slope of HBsAg decline). The HBsAg decline was larger in those patients who became HBeAg negative, irrespective of the treatment regimen. A decline in HBsAg was confined to ETV-treated patients with elevated baseline alanine aminotransferase (ALT) levels, whereas HBsAg decline was not associated with baseline ALT in patients treated with PEG-IFN. Within the HBeAg-negative population, PEG-IFN induced a significant HBsAg decline, while HBsAg did not decrease in ETV-treated patients (0.56 versus -0.10 log IU/ml, p<0.001). Both in HBeAg-positive and HBeAg-negative patients, the decline in serum HBV DNA was larger in patients who received ETV as compared to patients treated with PEG-IFN. CONCLUSIONS: In HBeAg-positive patients, the decline in serum HBsAg is mainly confined to patients who clear HBeAg, by either PEG-IFN or ETV treatment. In HBeAg-negative patients, PEG-IFN therapy resulted in a significant reduction in HBsAg levels, whereas HBsAg did not decrease in ETV-treated patients.