Friday, September 29, 2023

Duration of humoral immunity from smallpox vaccination and its cross-reaction with Mpox virus – Signal Transduction and Targeted Therapy

The global mpox outbreak in the shadow of the COVID-19 pandemic has recently drawn more attention. The mpox cases have surged in the last month in China since the whole population has returned to normal life due to the successful control of COVID-19 in Jan. 2023. Although safe and effective vaccines are critically needed to provide protection against MPXV infections, no clinically validated MPXV-specific vaccines are yet available. Smallpox vaccines have been proven to be effective in preventing MPXV infections due to the high genomic homology between the two viruses. However, the eradication of smallpox around the world has made more people vulnerable to MPXV infection, and mpox has gradually become the most significant zoonotic threat to human beings. The immunity level of vaccinated individuals has declined over time, and those younger than 43 years old as of 2023 have not received smallpox vaccination, which may be one of the main reasons for the re-emergence of mpox. To assess the level of residual immunity to smallpox in those people, it is crucial to evaluate the immunological susceptibility to MPXV, providing important clues for revaccination smallpox vaccines and the development of MPXV-specific vaccines in the current mpox outbreak.

Previous studies have demonstrated that virus-specific antibodies are necessary and sufficient to protect against lethal MPXV challenge.22 Neutralizing antibody was identified as an important correlate of protection against smallpox. Two studies indicated that high levels of neutralizing antibodies may be associated with protective immunity against smallpox. One of the two demonstrated that subjects who were in contact with smallpox victims possessing vaccinia virus neutralizing titers<1:32 were more susceptible to smallpox infection (3 of 15, or 20% of contacts infected) compared with subjects with antibody titers of ≥1:32 (0 of 127 or <1% of contacts infected).28 In another study, the titer of neutralizing Ab against vaccinia virus in human serum was thought to be at least 1:20 to provide protection against smallpox.29 However, the available cutoff values for preexisting antibody levels in humans were reported during the period of endemic smallpox circulation, which may not be relevant to the current population. In this study, we evaluated the vaccinia-specific IgG level and neutralizing antibody titers in 294 volunteers, and we found that humoral immunity from the smallpox vaccine in the Chinese population still remains, and VTT-specific NAb level wanes with age. Our results are consistent with previous studies showing that smallpox vaccine-induced immunity wanes with time,12,13,14 and those with low or no VTT-specific antibodies are more susceptible when exposed to MPXV and may need priority vaccination, such people born post-1981 in China.

VTT has played a critical role in the eradication of smallpox in China.25 Therefore, the titers of VTT-specific IgG were detected, and we found that the proportion of plasma samples positive for VTT-specific IgG increased with age, showing that the majority of the Chinese population in pre-1981 still retained the binding antibody response to vaccinia after vaccination for 42 or more years. Furthermore, the VTT-specific NAbs were also positive (PRNT50 ≥ 1:16) in 18.18% (20/110) of individuals older than 42 years, but the positive rate of anti-VTT NAb was slightly lower in people aged 54–63 years than in those aged 43–53 years. Thus, the current populations in China who received the smallpox vaccine decades ago still retain some humoral immunity against VTT, and VTT-specific NAb level declines with age.

Due to genetic and antigenic homology, smallpox vaccines have historically been used to prevent or reduce the severity of mpox.25,30 However, with the decline in VTT-specific antibody response, whether residual immunity among Chinese people could still provide cross-protection against mpox remains unknown. A number of MPXV envelope proteins, such as MIR, A35R, B6R, and A29L (the MPXV orthologs of the VACV L1R, A33R, and A27L genes, respectively), have been identified as targets of neutralizing antibodies.31 In this study, we detected the IgG levels of MPXV surface proteins MIR, A35R, B6R, and A29L and found that the population with positive anti-A35R/B6R/A29L in pre-1981 who should have received smallpox vaccination has a much higher positive proportion than that in people younger than 43 years old who probably have not been vaccinated. In particular, people 54–63 years old have a high proportion of antibodies targeting the A35R or B6R antigen. Therefore, the majority of the smallpox vaccine-immunized population still maintains certain levels of MPXV-specific antibodies, especially those targeting the A35R and B6R antigens. Moreover, the plasma samples positive for VTT were also positive for two or three antigens of A35R, B6R, and A29L, and the titers of VTT-specific IgG and A35R-specific IgG, B6R-specific IgG, and A29L-specific IgG were linearly correlated (p < 0.0001). However, the positive rate of anti-M1R was relatively low in all subjects, and the proportion with positive anti-A29L and anti-M1R is much higher than that with positive anti-A35R and anti-B6R in the 54- to 63-year-old group, which is contrary to the level of VTT-specific NAbs. We speculated that the binding abilities of A29L and MIR were slightly higher than those of A35R and B6R antigens,32 and as the anti-A29L and MIR levels declined, the NAb levels also waned. Interestingly, some younger people aged 19–42 years were VTT negative but were positive for both A35R and B6R antigens, and the proportion in those was higher than that in people aged 43–53 years. This may be due to other orthopoxvirus infections (such as CPXV) and acquired cross-protective immunity against MPXV. The above phenomenon also suggests that people immunized with the smallpox vaccine are less likely to be infected with other poxviruses.

Although this remaining immunity from smallpox vaccination may not provide full protection against MPXV infection, it is likely to decrease the probability of severe and fatal disease and relieve clinical symptoms after infection. However, to acquire more complete information regarding the immunity level against MPXV among the Chinese population, further investigations are required in terms of increasing the sample size and evaluating the live MPXV neutralizing antibody levels and the cellular immune response after vaccination against smallpox. Furthermore, a global mpox outbreak is currently primarily affecting gay, bisexual, and other men who have sex with men,33 which are high-risk populations. The immunity level of high-risk populations to MPXV is required to be investigated.

In summary, our results indicate that most Chinese populations still maintain VTT-specific IgG antibody for 42 or more years after smallpox vaccination and could provide mpox virus-specific IgG antibodies. Our findings contribute to prioritizing the anti-MPXV strategy and prevention in the population under 43 years of age, especially high-risk populations, such as gay, bisexual, or other men who have sex with men, as well as immunocompromised subjects.

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