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NDV-HXP-S is a recombinant Newcastle disease virus–based vaccine against SARS-CoV-2, which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that used for the production of the vast majority of influenza virus vaccines. Here, we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a phase 1 clinical study in Thailand. The SARS-CoV-2 neutralizing and spike protein binding activity of NDV-HXP-S postvaccination serum samples was compared to that of samples from mRNA BNT162b2 (Pfizer) vaccinees. Neutralizing activity of sera from NDV-HXP-S vaccinees was comparable to that of BNT162b2 vaccinees, whereas spike protein binding activity of the NDV-HXP-S vaccinee samples was lower than that of sera obtained from mRNA vaccinees. This led us to calculate ratios between binding and neutralizing antibody titers. Samples from NDV-HXP-S vaccinees had binding to neutralizing activity ratios that were lower than those of BNT162b2 sera, suggesting that NDV-HXP-S vaccination elicits a high proportion of neutralizing antibodies and low non-neutralizing antibody titers. Further analysis showed that, in contrast to mRNA vaccination, which induces strong antibody titers to the receptor binding domain (RBD), the N-terminal domain, and the S2 domain, NDV-HXP-S vaccination induced an RBD-focused antibody response with little reactivity to S2. This finding may explain the high proportion of neutralizing antibodies. In conclusion, vaccination with inactivated NDV-HXP-S induces a high proportion of neutralizing antibodies and absolute neutralizing antibody titers that are comparable to those elicited by mRNA vaccination. A New(castle disease virus) vaccine for SARS-CoV-2: SARS-CoV-2 vaccines have been essential in combating the ongoing COVID-19 pandemic, but room for improvement remains. Here, Carreño et al. analyzed immune responses in individuals vaccinated with a Newcastle disease virus-based SARS-CoV-2 vaccine, NDV-HXP-S. This vaccine can be produced in embryonated chicken eggs, similar to the majority of influenza vaccines, making it readily translatable. The authors found that vaccination with NDV-HXP-S elicited a higher proportion of neutralizing antibodies against SARS-CoV-2 than vaccination with the BNT162b2 mRNA vaccine. NDV-HXP-S vaccinees also had a response more focused on the receptor binding domain. Together, these data highlight the promise of NDV-HXP-S, which has moved into a Phase III trial in Thailand. —CM [ABSTRACT FROM AUTHOR]