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The manufacturer of the Ad26.COV2.S vaccine against Covid-19 comments on recent reports of thrombosis, including cerebral venous sinus thrombosis, associated with severe thrombocytopenia in several recipients of the vaccine.

In this interim phase 1–2a trial of an adenovirus-based vaccine (Ad26.COV2.S), participants were divided into two age groups and received one or two injections of either a low-dose or high-dose vaccine or placebo. The vaccine elicited a local injection response in most patients and high titers of neutralizing antibodies in all vaccinated groups. In addition, T-cell responses were noted.

Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector containing the gene sequence that produces SARS-CoV-2 spike protein in a prefusion-stabilized conformation. In a randomized trial involving nearly 40,000 persons, vaccine efficacy was 66% against moderate to severe–critical Covid-19 and 85% against severe–critical Covid-19. Efficacy against the variant first identified in South Africa was 64% against moderate disease and 82% against severe–critical disease.

The Ad26.COV2.S vaccine 1 – 3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies 1 . However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I–IIa clinical trial 2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. Analysis of the immunogenicity of the Ad26.COV2.S vaccine against the B1.351 and P.1 SARS-CoV-2 variants of concern shows reduced neutralization antibody titres, but comparable T cell responses and antibody-dependent effector functions.

The randomized trial assessing the efficacy of a single injection of the Ad26.COV2.S showed 56.3% vaccine efficacy beginning 14 days after injection and 52.9% efficacy more than 28 days after injection against moderate to severe–critical Covid-19. Protection lasted at least 6 months without an added boost. Vaccination was associated with mild-to-moderate adverse effects.

A combination of adenovirus 26 and protein vaccines was used to deliver a prefusion stabilized RSV protein. RSV-related lower respiratory tract illness developed in fewer vaccine recipients than placebo recipients.

Current tuberculosis (TB)-control methods, which do not include an adequate vaccine, do not effectively block transmission of TB. Modeling studies show that mass vaccination campaigns using new vaccines could prevent 85.9 million new cases and 14.5 million deaths from 2015 through 2050 in southern Asia alone. After a dearth of many years, the development pipeline now includes 7 vaccine candidates that are being tested in humans. Two nonreplicating viral vectored vaccines have very recently entered the first phase IIb efficacy trial in infants (the first such trial in 80 years) and in human immunodeficiency virus-infected adults. Science is moving forward, but the scientific advancements need to be accompanied by political mobilization to ensure that the resources are available to develop, manufacture, and distribute the new vaccines and, thus, save millions of lives.

Protective efficacy of novel vaccine candidates in rhesus monkeys opens new paths for the development of an HIV-1 vaccine. Vaccines protect against virulent SIV Despite the recent demonstration of partial HIV-1 vaccine efficacy in humans, the immune responses required to protect against acquisition of infection remain unclear. Here, Barouch et al . demonstrate vaccine protection against acquisition of a stringent strain of simian immunodeficiency virus (SIV) in rhesus monkeys. Two candidate vaccines expressing the Gag, Pol and Env viral antigens were tested. They observe a delay in acquisition of SIV in vaccinated monkeys following repeated challenges with SIV MAC251 . Protection against acquisition is correlated with Env-specific antibody responses, which the authors postulate may be critical for delaying infection, although whether the antibodies are surrogates for protection or causal correlates is not yet clear. Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges 1 , 2 , 3 . Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV SME543 Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection 4 , 5 against repetitive, intrarectal SIV MAC251 challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

Background. One strategy for improving anti-tuberculosis (TB) vaccination involves the use of recombinant bacille Calmette-Guérin (rBCG) overexpressing protective TB antigens. rBCG30, which overexpresses the Mycobacterium tuberculosis secreted antigen Ag85b, was the first rBCG shown to induce significantly greater protection against TB in animals than parental BCG. Methods. We report here the first double-blind phase 1 trial of rBCG30 in 35 adults randomized to receive either rBCG30 or parental Tice BCG intradermally. Clinical reactogenicity was assessed, and state-of-the-art immunological assays were used to study Ag85b-specific immune responses induced by both vaccines. Results. Similar clinical reactogenicity occurred with both vaccines. rBCG30 induced significantly increased Ag85b-specific T cell lymphoproliferation, interferon (IFN)-γ secretion, IFN-γ enzyme-linked immunospot responses, and direct ex vivo intracellular IFN-γ responses. Additional flow cytometry studies measuring carboxyfluorescein succinimidyl ester dilution and intracellular cytokine production demonstrated that rBCG30 significantly enhanced the population of Ag85b-specific CD4+ and CD8+ T cells capable of concurrent expansion and effector function. More importantly, rBCG30 significantly increased the number of Ag85b-specific T cells capable of inhibiting intracellular mycobacteria. Conclusions. These results provide proof of principal that rBCG can safely enhance human TB immunity and support further development of rBCG overexpressing Ag85b for TB vaccination.

Yasir Skeiky and Jerry Sadoff outline the current state of play in the development of effective vaccines against Mycobacterium tuberculosis . Promising strategies include the use of modified recombinant BCG, live attenuated M. tuberculosis and subunit vaccines alone or in prime?boost regimens to optimize immunity and vaccine safety. Tuberculosis (TB), an ancient human scourge, is a growing health problem in the developing world. Approximately two million deaths each year are caused by TB, which is the leading cause of death in HIV-infected individuals. Clearly, an improved TB vaccine is desperately needed. Heterologous prime?boost regimens probably represent the best hope for an improved vaccine regimen to prevent TB. This first generation of new vaccines might also complement drug treatment regimens and be effective against reactivation of TB from the latent state, which would significantly enhance their usefulness.