mRNA vaccines expressing malaria transmission-blocking antigens Pfs25 and Pfs230D1 induce a functional immune response.

Malaria transmission-blocking vaccines (TBV) are designed to inhibit the sexual stage development of the parasite in the mosquito host and can play a significant role in achieving the goal of malaria elimination. Preclinical and clinical studies using protein-protein conjugates of leading TBV antigens Pfs25 and Pfs230 domain 1 (Pfs230D1) have demonstrated the feasibility of TBV. Nevertheless, other promising vaccine platforms for TBV remain underexplored. The recent success of mRNA vaccines revealed the potential of this technology for infectious diseases. We explored the mRNA platform for TBV development. mRNA constructs of Pfs25 and Pfs230D1 variously incorporating signal peptides (SP), GPI anchor, and Trans Membrane (TM) domain were assessed in vitro for antigen expression, and selected constructs were evaluated in mice. Only mRNA constructs with GPI anchor or TM domain that resulted in high cell surface expression of the antigens yielded strong immune responses in mice. These mRNA constructs generated higher transmission-reducing functional activity versus the corresponding alum-adjuvanted protein-protein conjugates used as comparators. Pfs25 mRNA with GPI anchor or TM maintained >99% transmission reducing activity through 126 days, the duration of the study, demonstrating the potential of mRNA platform for TBV.

Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

Leveraging automated approaches to categorize birth defects from abstracted birth hospitalization data.

BACKGROUND: The Surveillance for Emerging Threats to Pregnant People and Infants Network (SET-NET) collects data abstracted from medical records and birth defects registries on pregnant people and their infants to understand outcomes associated with prenatal exposures. We developed an automated process to categorize possible birth defects for prenatal COVID-19, hepatitis C, and syphilis surveillance. By employing keyword searches, fuzzy matching, natural language processing (NLP), and machine learning (ML), we aimed to decrease the number of cases needing manual clinician review. METHODS: SET-NET captures International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes and free text describing birth defects. For unstructured data, we used keyword searches, and then conducted fuzzy matching with a cut-off match score of ≥90%. Finally, we employed NLP and ML by testing three predictive models to categorize birth defect data. RESULTS: As of June 2023, 8326 observations containing data on possible birth defects were submitted to SET-NET. The majority (n = 6758 [81%]) were matched to an ICD-10-CM code and 1568 (19%) were unable to be matched. Through keyword searches and fuzzy matching, we categorized 1387/1568 possible birth defects. Of the remaining 181 unmatched observations, we correctly categorized 144 (80%) using a predictive model. CONCLUSIONS: Using automated approaches allowed for categorization of 99.6% of reported possible birth defects, which helps detect possible patterns requiring further investigation. Without employing these analytic approaches, manual review would have been needed for 1568 observations. These methods can be employed to quickly and accurately sift through data to inform public health responses.

Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models.

Despite the success of the widely used attenuated yellow fever (YF) vaccine, its global supply remains a substantial barrier to implementing vaccination campaigns in endemic regions and combating emerging epidemics. In A129 mice and rhesus macaques, we evaluated the immunogenicity and protective activity of messenger RNA (mRNA) vaccine candidates encapsulated in lipid nanoparticles, expressing the pre-membrane and envelope proteins or the non-structural protein 1 of YF virus. Vaccine constructs induced humoral and cell-mediated immune responses in mice, resulting in protection against lethal YF virus infection after passive administration of serum or splenocytes from vaccinated mice. Vaccination of macaques induced sustained high humoral and cellular immune responses for at least 5 months after the second dose. Our data demonstrate that these mRNA vaccine candidates can be considered an attractive addition to the licensed YF vaccine supply based on the induction of functional antibodies correlating with protection and T-cell responses; they could alleviate the limited supply of current YF vaccines, mitigating future YF epidemics.

Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models.

Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve control of the COVID-19 pandemic. We compare monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein in a transgenic mouse and a Wistar rat model. The blended low-dose bivalent mRNA vaccine contains half the mRNA of each respective monovalent vaccine, but induces comparable neutralizing antibody titres, enrichment of lung-resident memory CD8+ T cells, antigen-specific CD4+ and CD8+ responses, and protects transgenic female mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduces viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized female Wistar rats also contain neutralizing antibodies against the B.1.1.529 (Omicron BA.1 and BA.5) variants. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins are feasible approaches for extending the coverage of vaccines for emerging and co-circulating SARS-CoV-2 variants.

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-Based Omicron COVID-19 Vaccination in Small Animal Models.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron and its subvariants (BA.2, BA.4, BA.5) represented the most commonly circulating variants of concern (VOC) in the coronavirus disease 2019 (COVID-19) pandemic in 2022. Despite high vaccination rates with approved SARS-CoV-2 vaccines encoding the ancestral spike (S) protein, these Omicron subvariants have collectively resulted in increased viral transmission and disease incidence. This necessitates the development and characterization of vaccines incorporating later emerging S proteins to enhance protection against VOC. In this context, bivalent vaccine formulations may induce broad protection against VOC and potential future SARS-CoV-2 variants. Here, we report preclinical data for a lipid nanoparticle (LNP)-formulated RNActive® N1-methylpseudouridine (N1mΨ) modified mRNA vaccine (CV0501) based on our second-generation SARS-CoV-2 vaccine CV2CoV, encoding the S protein of Omicron BA.1. The immunogenicity of CV0501, alone or in combination with a corresponding vaccine encoding the ancestral S protein (ancestral N1mΨ), was first measured in dose-response and booster immunization studies performed in Wistar rats. Both monovalent CV0501 and bivalent CV0501/ancestral N1mΨ immunization induced robust neutralizing antibody titers against the BA.1, BA.2 and BA.5 Omicron subvariants, in addition to other SARS-CoV-2 variants in a booster immunization study. The protective efficacy of monovalent CV0501 against live SARS-CoV-2 BA.2 infection was then assessed in hamsters. Monovalent CV0501 significantly reduced SARS-CoV-2 BA.2 viral loads in the airways, demonstrating protection induced by CV0501 vaccination. CV0501 has now advanced into human Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT05477186).

Mpox Cases Among Cisgender Women and Pregnant Persons - United States, May 11-November 7, 2022.

Monkeypox (mpox) cases in the 2022 outbreak have primarily occurred among adult gay, bisexual, and other men who have sex with men (MSM); however, other populations have also been affected (1). To date, data on mpox in cisgender women and pregnant persons have been limited. Understanding transmission in these populations is critical for mpox prevention. In addition, among pregnant persons, Monkeypox virus can be transmitted to the fetus during pregnancy or to the neonate through close contact during or after birth (2-5). Adverse pregnancy outcomes, including spontaneous abortion and stillbirth, have been reported in previous mpox outbreaks (3). During May 11-November 7, 2022, CDC and U.S. jurisdictional health departments identified mpox in 769 cisgender women aged ≥15 years, representing 2.7% of all reported mpox cases.† Among cases with available data, 44% occurred in cisgender women who were non-Hispanic Black or African American (Black), 25% who were non-Hispanic White (White), and 23% who were Hispanic or Latino (Hispanic). Among cisgender women with available data, 73% reported sexual activity or close intimate contact as the likely route of exposure, with mpox lesions most frequently reported on the legs, arms, and genitals. Twenty-three mpox cases were reported in persons who were pregnant or recently pregnant§; all identified as cisgender women based on the mpox case report form.¶ Four pregnant persons required hospitalization for mpox. Eleven pregnant persons received tecovirimat, and no adverse reactions were reported. Continued studies on mpox transmission risks in populations less commonly affected during the outbreak, including cisgender women and pregnant persons, are important to assess and understand the impact of mpox on sexual, reproductive, and overall health.

Epidemiologic and Clinical Features of Mpox in Transgender and Gender-Diverse Adults - United States, May-November 2022.

As of November 9, 2022, a total of 28,730 cases of monkeypox (mpox) had been reported in the United States,* primarily among adult cisgender men reporting recent male-to-male sexual contact (1). Transgender and gender-diverse persons, who constitute an estimated 0.5% of the U.S. adult population,† face unique health disparities and barriers to care (2-4). However, data on the epidemiologic and clinical features of Monkeypox virus infections in this population are limited (5). CDC analyzed U.S. case surveillance data on mpox cases in transgender and gender-diverse adults reported during May 17-November 4, 2022. During this period, 466 mpox cases in transgender and gender-diverse adults were reported, accounting for 1.7% of reported cases among adults. Most were in transgender women (43.1%) or gender-diverse persons (42.1%); 14.8% were in transgender men. Among 374 (80.3%) mpox cases in transgender and gender-diverse adults with information available on sexual or close intimate contact, 276 (73.8%) reported sexual or close intimate contact with a cisgender male partner during the 3 weeks preceding symptom onset. During the ongoing outbreak, transgender and gender-diverse persons have been disproportionately affected by mpox. Members of this population frequently reported recent sexual or close intimate contact with cisgender men, who might be in sexual networks experiencing the highest incidence of mpox. These findings highlight the importance of tailoring public health prevention and outreach efforts to transgender and gender-diverse communities and could guide strategies to reduce mpox transmission.

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro.

Recent evidence implicates a gut-first pathogenesis in the enteric nervous system (ENS) within a portion of PD patients, yet in vitro investigations have primarily focused on the central nervous system. Here, the preformed fibril (PFF) PD model is applied with co-administered groups of butyrate and lipopolysaccharide to model the effects of the local gut microbiome. Significant PFF uptake and retention occur in isolated rat enteric neurons compared to untreated controls resulting in increasing immunostained aggregate conformation-specific, alpha-synuclein (a-Syn) average intensity between 6 µg PFF and untreated controls. Cortical neurons significantly retain PFFs with an increase in aggregated a-Syn average intensity within all dosages. Differences in growth cone morphology but not dynamics in PFF-treated ENS cultures occur. Electrophysiological recordings via a microelectrode array (MEA) indicate no overall difference in spontaneous spike rate. However, only untreated controls respond to PD-relevant dopamine stimulus, while 1 µg PFF and control populations respond to stimulus with ENS-abundant acetylcholine. Finally, no differences in substance P levels-correlated with PD and neurodegeneration-are observed. Overall, these findings suggest the ENS retains PFF dosage absent acute loss in function, however, does experience changes in growth cone morphology and dopamine-stimulated activity.

Epidemiologic Features of the Monkeypox Outbreak and the Public Health Response - United States, May 17-October 6, 2022.

On May 17, 2022, the Massachusetts Department of Health announced the first suspected case of monkeypox associated with the global outbreak in a U.S. resident. On May 23, 2022, CDC launched an emergency response (1,2). CDC's emergency response focused on surveillance, laboratory testing, medical countermeasures, and education. Medical countermeasures included rollout of a national JYNNEOS vaccination strategy, Food and Drug Administration (FDA) issuance of an emergency use authorization to allow for intradermal administration of JYNNEOS, and use of tecovirimat for patients with, or at risk for, severe monkeypox. During May 17-October 6, 2022, a total of 26,384 probable and confirmed* U.S. monkeypox cases were reported to CDC. Daily case counts peaked during mid-to-late August. Among 25,001 of 25,569 (98%) cases in adults with information on gender identity,† 23,683 (95%) occurred in cisgender men. Among 13,997 cisgender men with information on recent sexual or close intimate contact,§ 10,440 (75%) reported male-to-male sexual contact (MMSC) ≤21 days preceding symptom onset. Among 21,211 (80%) cases in persons with information on race and ethnicity,¶ 6,879 (32%), 6,628 (31%), and 6,330 (30%) occurred in non-Hispanic Black or African American (Black), Hispanic or Latino (Hispanic), and non-Hispanic White (White) persons, respectively. Among 5,017 (20%) cases in adults with information on HIV infection status, 2,876 (57%) had HIV infection. Prevention efforts, including vaccination, should be prioritized among persons at highest risk within groups most affected by the monkeypox outbreak, including gay, bisexual, and other men who have sex with men (MSM); transgender, nonbinary, and gender-diverse persons; racial and ethnic minority groups; and persons who are immunocompromised, including persons with advanced HIV infection or newly diagnosed HIV infection.

Breast Milk Feeding of Infants at Birth Among People With Confirmed SARS-CoV-2 Infection in Pregnancy: SET-NET, 5 States, March 29, 2020-December 31, 2020.

Objectives. To describe prevalence of breast milk feeding among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and examine associations between breast milk feeding, timing of maternal infection before delivery, and rooming-in status during delivery hospitalization. Methods. We performed a retrospective cohort study using data from Massachusetts, Minnesota, Nebraska, Pennsylvania, and Tennessee of whether people with confirmed SARS-CoV-2 infection during pregnancy in 2020 initiated breast milk feeding at birth. Results. Among 11 114 (weighted number) people with SARS-CoV-2 infection in pregnancy, 86.5% (95% confidence interval [CI] = 82.4%, 87.6%) initiated breast milk feeding during birth hospitalization. People with infection within 14 days before delivery had significantly lower prevalence of breast milk feeding (adjusted prevalence ratio [APR] = 0.88; 95% CI = 0.83, 0.94) than did those with infection at least 14 days before delivery. When stratified by rooming-in status, the association between timing of infection and breast milk feeding remained only among infants who did not room in with their mother (APR = 0.77; 95% CI = 0.68, 0.88). Conclusions. Pregnant and postpartum people with SARS-CoV-2 infection should have access to lactation support and be advised about the importance of breast milk feeding and how to safely feed their infants in the same room. (Am J Public Health. 2022;112(S8):S787-S796. https://doi.org/10.2105/AJPH.2022.307023).

Optimised Non-Coding Regions of mRNA SARS-CoV-2 Vaccine CV2CoV Improves Homologous and Heterologous Neutralising Antibody Responses.

More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are circulating, highlighting the need to adapt vaccination strategies. Here, we compare the immunogenicity of a first-generation mRNA vaccine candidate, CVnCoV, with a second-generation mRNA vaccine candidate, CV2CoV, in rats. Higher levels of spike (S) protein expression were observed in cell culture with the CV2CoV mRNA than with the CVnCoV mRNA. Vaccination with CV2CoV also induced higher titres of virus neutralising antibodies with accelerated kinetics in rats compared with CVnCoV. Significant cross-neutralisation of the SARS-CoV-2 variants, Alpha (B.1.1.7), Beta (B.1.351), and the 'mink' variant (B1.1.298) that were circulating at the time in early 2021 were also demonstrated. In addition, CV2CoV induced higher levels of antibodies at lower doses than CVnCoV, suggesting that dose-sparing could be possible with the next-generation SARS-CoV-2 vaccine, which could improve worldwide vaccine supply.

mRNA vaccines induce rapid antibody responses in mice.

mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4 µg/mouse), but not DNA (50 µg/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks.

Prevalence of individual brain and eye defects potentially related to Zika virus in pregnancy in 22 U.S. states and territories, January 2016 to June 2017.

During the Centers for Disease Control and Prevention's Zika Virus Response, birth defects surveillance programs adapted to monitor birth defects potentially related to Zika virus (ZIKV) infection during pregnancy. Pregnancy outcomes occurring during January 2016 to June 2017 in 22 U.S. states and territories were used to estimate the prevalence of those brain and eye defects potentially related to ZIKV. Jurisdictions were divided into three groups: areas with widespread ZIKV transmission, areas with limited local ZIKV transmission, and areas without local ZIKV transmission. Prevalence estimates for selected brain and eye defects and microcephaly per 10,000 live births were estimated. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for areas with widespread and limited ZIKV transmission compared with areas without local ZIKV transmission. Defects with significantly higher prevalence in areas of widespread transmission were pooled, and PRs were calculated by quarter, comparing subsequent quarters to the first quarter (January-March 2016). Nine defects had significantly higher prevalence in areas of widespread transmission. The highest PRs were seen in intracranial calcifications (PR = 12.6, 95% CI [7.4, 21.3]), chorioretinal abnormalities (12.5 [7.1, 22.3]), brainstem abnormalities (9.3 [4.7, 18.4]), and cerebral/cortical atrophy (6.7 [4.2, 10.8]). The PR of the nine pooled defects was significantly higher in three quarters in areas with widespread transmission. The largest difference in prevalence was observed for defects consistently reported in infants with congenital ZIKV infection. Birth defects surveillance programs could consider monitoring a subset of birth defects potentially related to ZIKV in pregnancy.

SARS-CoV-2 infections among neonates born to pregnant people with SARS-CoV-2 infection: Maternal, pregnancy and birth characteristics.

BACKGROUND: Multiple reports have described neonatal SARS-CoV-2 infection, including likely in utero transmission and early postnatal infection, but published estimates of neonatal infection range by geography and design type. OBJECTIVES: To describe maternal, pregnancy and neonatal characteristics among neonates born to people with SARS-CoV-2 infection during pregnancy by neonatal SARS-CoV-2 testing results. METHODS: Using aggregated data from the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) describing infections from 20 January 2020 to 31 December 2020, we identified neonates who were (1) born to people who were SARS-CoV-2 positive by RT-PCR at any time during their pregnancy, and (2) tested for SARS-CoV-2 by RT-PCR during the birth hospitalisation. RESULTS: Among 28,771 neonates born to people with SARS-CoV-2 infection during pregnancy, 3816 (13%) underwent PCR testing and 138 neonates (3.6%) were PCR positive. Ninety-four per cent of neonates testing positive were born to people with infection identified ≤14 days of delivery. Neonatal SARS-CoV-2 infection was more frequent among neonates born preterm (5.7%) compared to term (3.4%). Neonates testing positive were born to both symptomatic and asymptomatic pregnant people. CONCLUSIONS: Jurisdictions reported SARS-CoV-2 RT-PCR results for only 13% of neonates known to be born to people with SARS-CoV-2 infection during pregnancy. These results provide evidence of neonatal infection identified through multi-state systematic surveillance data collection and describe characteristics of neonates with SARS-CoV-2 infection. While perinatal SARS-CoV-2 infection was uncommon among tested neonates born to people with SARS-CoV-2 infection during pregnancy, nearly all cases of tested neonatal infection occurred in pregnant people infected around the time of delivery and was more frequent among neonates born preterm. These findings support the recommendation for neonatal SARS-CoV-2 RT-PCR testing, especially for people with acute infection around the time of delivery.

Identifying possible inaccuracy in reported birth head circumference measurements among infants in the US Zika Pregnancy and Infant Registry.

BACKGROUND: The US Zika Pregnancy and Infant Registry (USZPIR) monitors infants born to mothers with confirmed or possible Zika virus infection during pregnancy. The surveillance case definition for Zika-associated birth defects includes microcephaly based on head circumference (HC). METHODS: We assessed birth and follow-up data from infants with birth HC measurements <3rd percentile and birthweight ≥10th percentile to determine possible misclassification of microcephaly. We developed a schema informed by literature review and expert opinion to identify possible HC measurement inaccuracy using HC growth velocity and longitudinal HC measurements between 2 and 12 months of age. Two or more HC measurements were required for assessment. Inaccuracy in birth HC measurement was suspected if growth velocity was >3 cm/month in the first 3 months or HC was consistently >25th percentile during follow-up. RESULTS: Of 6,799 liveborn infants in USZPIR, 351 (5.2%) had Zika-associated birth defects, of which 111 had birth HC measurements <3rd percentile and birthweight ≥10th percentile. Of 84/111 infants with sufficient follow-up, 38/84 (45%) were classified as having possible inaccuracy of birth HC measurement, 19/84 (23%) had HC ≥3rd percentile on follow-up without meeting criteria for possible inaccuracy, and 27/84 (32%) had continued HC <3rd percentile. After excluding possible inaccuracies, the proportion of infants with Zika-associated birth defects including microcephaly decreased from 5.2% to 4.6%. CONCLUSIONS: About one-third of infants in USZPIR with Zika-associated birth defects had only microcephaly, but indications of possible measurement inaccuracy were common. Implementation of this schema in longitudinal studies can reduce misclassification of microcephaly.

Zika-Associated Birth Defects Reported in Pregnancies with Laboratory Evidence of Confirmed or Possible Zika Virus Infection - U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine.

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 µg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.

mRNA Vaccines Induce Rapid Antibody Responses in Mice.

mRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks. IMPORTANCE: mRNA vaccines can be developed and produced in record time. Here we demonstrate induction of rapid antibody responses by mRNA vaccines encoding two different viral antigens by day 5 following immunization in mice. The rapid immune kinetics of mRNA vaccines can be an advantageous property that makes them well suited for rapid control of infectious disease outbreaks.